Molecular Neurobiology

, Volume 47, Issue 2, pp 561–574 | Cite as

Inflammation and α-Synuclein’s Prion-like Behavior in Parkinson's Disease—Is There a Link?

  • Carla M. Lema ToméEmail author
  • Trevor Tyson
  • Nolwen L. Rey
  • Stefan Grathwohl
  • Markus Britschgi
  • Patrik BrundinEmail author
Open Access


Parkinson’s disease patients exhibit progressive spreading of aggregated α-synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of α-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded α-synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of α-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of α-synuclein and that novel anti-inflammatory therapies targeting this mechanism could slow disease progression.


α-Synuclein Neuroinflammation Prion-like Parkinson's disease Synucleinopathies Dual-hit hypothesis Proteinopathy 


Age-related neurodegenerative disorders, including Parkinson’s disease (PD), are neuropathologically characterized by accumulation of misfolded proteins and the loss of neurons along with sustained neuroinflammation. Clinically, PD patients experience both motor (e.g., bradykinesia, resting tremor, rigidity, and postural instability) and non-motor symptoms (e.g., hyposmia, constipation, sleep disturbances, depression, and dementia). Age is considered the single greatest risk factor for developing PD with 4–5 % of people over 85 years developing the disease [1]. In PD, dopamine-producing neurons in the substantia nigra pars compacta (SNpc) die and there is a concomitant decrease of dopaminergic innervation in the striatum. Furthermore, alpha-synuclein (α-syn) misfolds and forms intraneuronal aggregates in several brain regions. α-Syn is a 140-amino acid protein encoded by a single gene located in chromosome 4 [2] and was first described to be present in the nucleus and presynaptic terminals of normal neurons [3]. In PD and the related synucleinopathies multiple system atrophy and dementia with Lewy bodies, misfolded and aggregated α-syn forms intra-cytoplasmic inclusions. In PD, they are located in neurons and are called Lewy bodies (LB) and Lewy neurites (LN) [4, 5, 6]. The idea that α-syn plays a central role in PD pathogenesis is supported by the link between three missense α-syn mutations, i.e., Ala53Thr [7], Ala30Pro [8], and Glu46Lys [9] and autosomal dominant early-onset PD. Furthermore, multiplications of the gene cause familial forms of neurodegenerative disease with parkinsonian features [10] and certain SNPs in the α-syn promoter are associated with increased risk for PD [11]. Recent studies suggest that prion-like cell-to-cell transfer of possibly misfolded α-syn contributes to the spreading of neuropathology from one brain region to the next [12, 13, 14, 15, 16, 17].

Although there is no consensus on the causes of sporadic PD, neuroinflammation appears to play an important role (reviewed in [18]). Several questions still remain: how, if at all, is neuroinflammation linked to α-syn misfolding and aggregation? For example, does neuroinflammation trigger α-syn misfolding or does aggregated α-syn cause microglia activation and neuroinflammation? Furthermore, does neuroinflammation promote cell-to-cell transfer of α-syn and seeding and development of new α-syn aggregates? Alternatively, does the inflammatory process delay the prion-like spread of α-syn? In this review, we will discuss various aspects that drive pathological alterations of α-syn with a special focus on how neuroinflammation might affect the different steps.

Involvement of Immune Pathways in the Brain of Patients with Parkinson’s Disease

Inflammation is a specialized reaction of the body to harmful agents or insults to tissue. Inflammatory processes in the nervous system are called "neuroinflammation" and they are characteristic to most neurodegenerative diseases, including PD. Classically, inflammation and neuroinflammation involve innate and adaptive immune responses that are regulated by secreted factors (e.g., cytokines, chemokines, complement proteins, acute phase proteins, reactive oxygen species (ROS), and arachidonate metabolites; reviewed in [19, 20]). Interestingly, genetic alterations in several immune function-related genes (e.g., DJ-1, leucine-rich repeat protein kinase-2 (LRRK2) and HLA-DR) can cause familial PD or increase the risk of developing PD (all studies and meta-analyses collected in This points to a key role for immune pathways in the pathogenetic mechanisms of PD which are possibly triggered by aging, oxidative stress, or abnormal forms of α-syn (reviewed in [21]).

Microglia and astrocytes are resident immune cells of the brain. The expression of specific markers associated with these cells (typically Iba-1, CD11b, and MHC class II for microglia, GFAP for astrocytes) increases with severity of neuroinflammation. Positron emission tomography imaging studies employing microglia-specific markers point to an early involvement and cerebral propagation of neuroinflammation in PD [22, 23]. Histological analysis of the substantia nigra in PD patients shows activated microglia [24, 25, 26], a high density of astrocytes [27], and in some cases also infiltrating T lymphocytes [26, 28]. Furthermore, postmortem PD brains exhibit increased levels of tumor necrosis factor (TNF) [29] and interleukin (IL)-1 and IL-6 [30]. The cerebrospinal fluid (CSF) of PD patients differs from that collected from Alzheimer’s disease (AD) patients, other neurodegenerative disorders or healthy individuals [31]. The CSF levels of transforming growth factor β1 and 2 (TGFβ1 and TGFβ2) [32] and ratios between amyloid-β (Aβ) 42 with fractalkine/CX3CL1 [33], as well as levels of complement factors C3 and fH [34], are all altered in PD. Whether the clinical findings should be taken as evidence that neuroinflammation directly contributes to neurodegeneration in PD is not clear. The secreted factors and activated immune cells are not just potentially neurotoxic, but can also exert neuroprotective effects in neurodegenerative disorders (reviewed in [35, 36]).

In summary, signs of neuroinflammation and genetic links between PD and immune function point to a possible role of immune pathways in PD. Whether inflammation is beneficial or detrimental in this context remains unclear and we think it is pertinent to ask the question what role inflammation could specifically play in propagation of synucleinopathy in PD.

Recent Updates About the Link Between α-Synuclein Aggregation and the Effect of Inflammation

It has been hypothesized that inflammation triggers, or at least contributes to, the development of α-syn pathology [12]. Indeed, in cellular assays, misfolded α-syn species can trigger activation of microglia [37, 38, 39, 40, 41, 42], one of the hallmarks of the neuroinflammatory process. Although a specific receptor for α-syn binding to microglia is still unknown, these cells can take up extracellular α-syn [43, 44] that in turn triggers the release of soluble immune modulators. The vulnerability of dopaminergic neurons to inflammation has also been linked to α-syn, as genetic ablation of α-syn in animal models decreases the sensitivity of these cells to inflammatory challenges [45]. Factors released from activated microglia can further enhance oxidative stress, protein misfolding, and aggregation, creating a positive feedback loop promoting degeneration of dopaminergic cells [46, 47]. Together, it remains unclear whether α-syn aggregation is a cause or consequence of inflammation.

Approximately 90 % of α-syn found in LBs is constitutively phosphorylated at serine 87 (S87-P) and serine 129 (S129-P). By contrast, less than 5 % of α-syn is phosphorylated at serine 129 in healthy human brain [48, 49, 50]. Phosphorylation of α-syn in neuronal cell lines has been linked to detrimental activation of microglia in mixed cell culture systems [51], but whether phosphorylation of α-syn induces inflammation or vice versa is not fully understood. Furthermore, the precise roles of phosphorylation or other post-translational modifications of α-syn for neurotoxicity, formation of aggregates, and activation of microglia are not clear, with different studies reporting conflicting results [52, 53, 54, 55].

Nitrated forms of α-syn have previously been suggested to be crucial to the pathogenesis of synucleinopathies [56] and nitrated α-syn can trigger inflammation and microglia activation [57, 58]. One study has shown that nitrated α-syn may be able to recruit peripheral leukocytes in cervical lymph nodes in a toxin-based (systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, (MPTP)) mouse model of PD. The same study also shows that adoptive transfer of T cells from syngeneic mice immunized with nitrated α-syn worsens dopaminergic neuron loss after MPTP treatment of recipient mice [57]. This indicates that certain adaptive immune mechanisms could play a role in PD pathobiology.

A recent study suggests that α-syn may be modified by inflammation caused by expression of human wild-type or mutant P301L Tau [59]. Both forms of Tau cause microglial changes and increase IL-6 and TNF-α levels while also increasing the levels of endogenous α-syn and S129-P α-syn.

Inflammation and aggregation of α-syn are dynamically interlinked and this interaction probably plays a key role in the pathogenesis of PD. As discussed in this review, there is increasing evidence that α-syn aggregation may be initiated by a seeding mechanism that could spread throughout neurons in a prion-like fashion possibly involving other amyloidogenic proteins. For example, fragments of α-syn are commonly found in Aβ plaques in the brain of AD patients [60], and certain rare mutations leading to familial forms of AD have been associated with LB pathology as well [61, 62]. Aggregation of α-syn and Aβ can trigger neuroinflammation, e.g., it activates microglia (for reviews see [63, 64]). Oxidative stress produced by neuroinflammation is reported to be a cellular consequence of α-syn aggregation, and excessive levels of free ROS can trigger more inflammation and α-syn aggregation [65, 66, 67]. This vicious feed-forward loop of aggregation-induced neuroinflammation that in turn causes more aggregation may be a central mechanism in the pathogenesis of PD and other proteinopathies of the brain.

The NAD-dependent deacetylase, sirtuin 1 (SIRT1), has been recently identified as a possible regulator of α-syn aggregation. Sirtuins are known to have anti-aging effects in nematodes and it is suggested that this family of enzymes may also play an important role in the regulation of inflammation (reviewed in depth by Galli et al. [68]). Recently, it was demonstrated that overexpression of SIRT1 in A53T α-syn transgenic mice increases their lifespan and reduces α-syn aggregation, and conversely, knocking-out SIRT1 has the opposite effect [69]. The underlying mechanism has been suggested to be lack of SIRT1-regulated activation of molecular chaperons, which leads to aggregation of α-syn. Thus, sirtuins affect both α-syn aggregation and inflammation and could provide a molecular link between these two processes in PD.

The development and maintenance of dopaminergic neurons is regulated by the orphan receptor Nurr1 [70]. In addition to its role in neurons, loss of Nurr1 also disinhibits the NF-kB signaling cascade in astrocytes and microglia leading to increased secretion of neurotoxic mediators by these cells thereby promoting the loss of dopaminergic neurons in a mouse model of PD [71]. Rare mutations in Nurr1 have been associated with a late-onset familial form of PD, which presents with reduced expression of Nurr1 in somatic cells including peripheral immune cells [72]. This link between Nurr1, inflammation, and PD phenotype is intriguing, but it remains to be shown whether it is relevant to α-syn aggregation.

Spread of Synucleinopathy and Progression of Parkinson’s Disease

The extent of α-syn pathology in the brain is believed to correlate to neurological disease stage [73]. Thus, just as the progression of symptoms tends to follow a predictable pattern, e.g., with certain non-motor symptoms preceding the onset of motor dysfunction, the progression of neuropathological changes are believed to follow a highly replicable pattern. Postulated by Braak and colleagues, this progression is divided into six stages in PD, starting first with the simultaneous appearance of α-syn aggregates in anterior olfactory structures and the vagal nerve. Thereafter, the pathology spreads rostrally, indicated by LNs and to some extent LBs. During stage 2, the pathology manifests itself in the caudal raphe nucleus, in the gigantocellular reticular nucleus, and in the coeruleus–subcoeruleus complex. It is not until stage 3 where it appears in the substantia nigra. At stage 4, lesions are detected in proencephalic regions and finally reach areas of neocortex and prefrontal cortex at the last stages [74]. This progressive pattern of appearance of α-syn aggregates in the brain suggests two possible routes for the spread of synucleinopathy into the brain following long and unmyelinated axonal projections, with a retrograde or anterograde progression [75]: first, the gastrointestinal route from the enteric nervous system (ENS) to the central nervous system (CNS) via dorsal motor neurons of the vagus (DMV) and the intermediolateral nucleus of the spinal cord [76, 77, 78]; and second, the olfactory route, from the olfactory bulb to the midbrain via other olfactory areas and the limbic system [79].

Several groups have debated the validity of the notion of progression of synucleinopathy and report a broad range of roughly 50–80 % of cases concurring with Braak’s staging [80, 81, 82] or concluding that it can be readily applied to most subjects [83]. In addition, other clinical studies on metabolic, structural, and functional data revealed that neuronal populations are differentially vulnerable to α-syn pathology and hence dysfunction is not in accordance to the proposed staging system [84]. Despite the controversy about the interpretation of neuropathology linked to clinical symptoms, these [80, 81, 82] and other studies [85, 86, 87] have led to the proposal of a unified staging system for all Lewy body disorders [88].

Interestingly, an estimated proportion of 90 % of PD patients exhibit olfactory deficits [89, 90, 91]. Several studies detected olfactory deficits early in the course of the disease, before the appearance of motor symptoms (for review, see [92]). Olfactory disturbances occur both in familial and sporadic forms of PD [90]. Histological studies in PD have also revealed a high degree of degeneration of olfactory cells, especially in the anterior olfactory nucleus (AON), which has been correlated to disease duration and LB load in the AON and olfactory bulb (OB) [90]. Thus, it has been proposed that PD might be primarily a disorder of olfaction [93] and that the olfactory pathways should be of high interest to study early PD stages.

Other histological studies in pre-symptomatic subjects, who go on to develop PD later in life, or PD patients with colonic bacterial infection, demonstrate pathological changes in the ENS that are associated with premotor symptoms involving the gastrointestinal (GI) tract and aggregation of α-syn in the ENS [94, 95, 96, 97]. Indeed, the majority of PD patients display accumulation of pathology-related phosphorylated α-syn in enteric neurons [98]. In line with these findings, the DMV connecting the ENS to the CNS has long been known to be severely affected in PD, potentially influencing GI functions [74]. GI-related non-motor symptoms therefore might represent a prodromal stage of PD.

Together, these data suggest that olfactory and enteric regions might be the starting points of the disease that spreads then to the CNS. Based on this idea, Hawkes et al. proposed a dual-hit hypothesis: a neurotropic pathogen could attack the nervous system from two routes—anterogradely through olfactory tracts and retrogradely through the vagal nerve—and this pathogen could enter the brain through the olfactory and enteric epithelium [79, 99]. Apart from targeting neurons directly, it is quite possible that a pathogen triggers local inflammatory processes, which could initiate synucleinopathy in olfactory and enteric regions leading to a progression of pathology. In the following sections, we describe how inflammation in the olfactory system and in the GI tract might be triggers that start the process of α-syn aggregation.

A Possible Role for Neuroinflammation in the Olfactory Bulb as a Trigger for PD

According to histological studies of PD patients' brains, α-syn abnormalities observed in anterior olfactory structures at Braak’s stage 1 are restricted to the AON and OB [74, 100]. More recent studies have demonstrated that after this step, the pathology spreads slowly into other olfactory regions like the piriform, periamygdaloid and entorhinal cortices, and the olfactory tubercle, without any progression in non-olfactory cortical areas [79].

Post-mortem studies investigating neuroinflammation in PD patients' brains have focused on midbrain structures. More extensive studies reported activated microglia also in the hippocampus and the temporal and entorhinal cortices [24]. Despite the involvement of olfactory regions in PD and the importance of neuroinflammation in PD, only one study has focused on the OB and demonstrated microgliosis in the OB of PD patients [101]. Due to its proximity to the olfactory epithelium and connections with the periphery, the olfactory system is very sensitive to exogenous pathogens, which might trigger local inflammation.

Sensibility of the Olfactory Epithelium and Olfactory Bulb to Inflammation

The olfactory epithelium is the first point of contact with the external environment. Mucocillaries of the olfactory epithelium act as a partial barrier against exogenous particles in the air [102, 103], but do not provide complete protection (for review see [104]). In humans, the thickness of the olfactory epithelium declines during aging [105] and thereby it might also become more permeable to particles and pathogens, increasing the risk of brain infections.

The organization of the human and rodent olfactory systems is similar [106] despite olfactory functions being less well developed in humans. In both species, the olfactory epithelium neurons, in contact with the external environment, project their axons into the glomerular layer of the OB, where they contact mitral cells, the relay cells of olfactory information. In rodents, these two types of cells have been shown to constitute a route for pathogen entry into the brain [104].

Further, in rodents, the OB contains a very dense population of microglial cells compared to other structures [107, 108], especially in the glomerular layer. A possible role of microglia in the OB is to phagocytose cellular debris [109] resulting from the high turnover of olfactory receptor neurons in the olfactory epithelium. Moreover, the microglia may also phagocytose OB interneurons [110] which are replaced throughout life in rodents, as well as possibly in humans, by adult neurogenesis [111, 112, 113]. Finally, OB microglia might also function as a sensor and barrier to exogenous particles and pathogens and could be involved in modulation and potentiation of neuroinflammation and associated disease [114, 115].

Among exogenous particles that can enter the OB, toxins (for review, see [116]), viruses, and particles (ultra-thin particles <100 nm, nanoparticles and microparticles) [99, 115, 117, 118, 119, 120, 121] have been widely studied. Studies in animal models have demonstrated that pathogens can be either blocked in the glomerular layer of the OB or spread though the axons of mitral cells to higher olfactory structures, such as the olfactory tubercle, amygdala, and olfactory cortex [114, 115].

Viruses Causing Inflammation in Olfactory Structures

The idea of a viral origin of PD was initially based on the observation that people born during the influenza pandemic 1918–1919 exhibit increased risk of developing parkinsonism, or so called post-encephalitic PD [122]. Viral infections during childhood have also been generally associated with higher likelihood of developing PD [123]. Moreover, diseases like asthma and seasonal and allergic rhinitis might be associated with PD [124], suggesting that chronic rhinitis, i.e., rhinitis-related inflammation, might promote the entry of neurotropic pathogens via the olfactory route [79]. Interestingly, influenza A virus has been detected in the SNpc of PD brains [125], and the interferon-induced protein MxA, which plays a role in defense against influenza virus, is associated with LBs [126].

The infection by neurotropic viruses through the olfactory route has been widely studied in experimental animals. Rodent studies demonstrate that various types of viruses entering via the olfactory epithelium can infect different cell types in the OB, leading to dysfunction in olfactory circuits, and to the activation of glial cells located in the outer layers of the OB [114, 117, 119, 127, 128, 129, 130, 131]. Depending on the viral dose [115], an immune reaction involving type I interferons (e.g., IFN-α and IFN-β) can sometimes block the propagation of the virus from the OB to other brain regions [132], but the immune reaction can also induce widespread inflammation. The effects of influenza virus infection on olfactory regions have been well described in rodents [117, 128, 133]. Shortly after infusion of a mouse-adapted human influenza virus in the nasal cavity of mice, the viral antigen is found in the OB (and more precisely in glial cells), but not in other brain regions. Production of cytokines, such as IL-1β and TNF-α, increased considerably at the onset of disease. The neuronal release of TNF-α and IL-1β was also increased in other brain regions, including those directly connected with the OB (piriform cortex, olfactory tubercle, central amygdala) and others, such as the hypothalamus. Hence, local infection in the OB can induce inflammatory signals in distant brain regions and can trigger global neuroinflammation.

As mentioned above, activated microglia can phagocytose pathogens and unwanted cells [134] acquire an antigen-presenting cell phenotype and contribute to the recruitment of T cells [135]. ROS and cytokines produced by microglia disrupt the blood brain barrier (BBB) [136, 137], and the effect of these inflammatory mediators is more pronounced in the olfactory epithelium and OB where the BBB already is more permeable than the BBB of other structures [138, 139, 140, 141]. Recently, the effect of TNF-α on BBB permeability was shown to favor CNS infection by the West Nile virus in mice [142]. Thus, neuroinflammation in the OB might increase BBB permeability, facilitating the penetration of exogenous pathogens and triggering microgliosis and leukocyte invasion into the OB, sparking off a vicious circle of inflammation. Possibly, a similar mechanism plays a role in humans, after a neurotropic virus infection entering through the nose.

Recently, Jang and colleagues [143] studied the consequences of H5N1 viral infection in C57Bl/6 mice by intranasal inoculation. The H5N1 avian influenza virus spread from the periphery to the CNS (via cranial nerves) and was found in neurons and astrocytes in the solitary nucleus, locus coeruleus, and in periglomerular and mitral cells of the OB. Twenty-one days post inoculation, the virus was no longer found in the brain, but the immune response persisted at least 2 months. Importantly, this study was the first to demonstrate the effect of viral infection on α-syn aggregation. An increase in cellular and secreted phosphorylated α-syn (pSer129) was observed in the OB, locus coeruleus, hippocampus, and brainstem. Moreover, aggregated α-syn was found in the hippocampus, cortex, and brainstem along with a loss of dopaminergic neurons in SNpc [143]. Taken together, these data point to the possibility that viral infection, maybe through inflammatory processes, can increase α-syn phosphorylation and induce/increase aggregation of α-syn in the brain.

Micro- and Nanoparticles Trigger Oxidative Stress and Inflammation in the OB

Certain metal particles might also be involved in PD, for example, LBs in the brain of PD patients have a high content of aluminum [144], or an enhanced risk to develop PD has been reported for subjects on a diet containing high quantities of iron [145]. Several studies have demonstrated that various types of particles (gold, 13C, manganese oxide, titanium dioxide, ferric oxide) can be inhaled, deposited on olfactory epithelium, tracheobronchial epithelium, and in lung alveoli in humans and mice (for review, see [121, 146]). Some particles then reach the CNS through olfactory epithelium and OB [120, 147, 148, 149, 150, 151] and may trigger inflammatory processes in the olfactory circuits. For example, in mice, an intranasal administration of Fe2O3 induces microglial proliferation, activation, and recruitment in the OB. In vitro, exposure to Fe2O3 leads to the release of ROS and NO by a microglia cell line that at the same time increases their proliferation [151]. Thus, chronic exposure to air particles, particularly in a polluted environment, could induce a chronic state of inflammation in olfactory and brain structures (for an extensive review on the involvement of viruses, particles, and pesticides in PD, see [152]).

Inflammation Process in the Olfactory Bulb: Local Consequences

Peripheral injection of lipopolysaccharide (LPS) is a widely used, but not very well understood, method to induce distant immune reactions in the rodent brain. Mori et al. and Ota et al. focused on olfactory regions and showed in mice a significant loss of cells in the OB and an increase in TNF-α and IκBα expression after peripheral LPS injection [153, 154]. Additionally, LPS administration increased expression of TNF receptors 1 and 2, and caspase 8 gene [154], as well as enhanced Fas expression [153]. Two other studies showed that TNF-α itself has deleterious effects on olfactory cells, causing dysfunction of olfactory neurons [155] and inhibiting regeneration of olfactory mucosa [156]. Moreover, when local inflammation in the OB after nasal instillation of a mycotoxin is coupled to a peripheral LPS injection, the expression of immune-stimulating genes is dramatically increased in the olfactory mucosa and the OB. This suggests that the effects of peripheral LPS could magnify apoptosis and inflammation in the olfactory epithelium and OB [118].

In summary, local inflammatory processes can lead to neuronal death and olfactory neuron dysfunction, which may translate into early olfactory impairments occurring in early PD. Thus, exposure to viruses and micro/nanoparticles during our lifetime may initiate chronic inflammation through the olfactory network, induce aggregation of α-syn, and cause damage and dysfunctions that accumulate over time. This may enhance early synucleinopathy in OB and contribute to PD initiation and progression (see Fig. 1).
Fig. 1

Possible initiation mechanism and spreading of synucleinopathy from the olfactory bulb to the brain. Pathogens or particles entering the olfactory epithelium spread to the olfactory bulb (OB) through axons of olfactory neurons. The pathogens induce an inflammatory response and oxidative stress in the OB and damage that accumulates overtime and induces α-syn misfolding and aggregation. α-Syn then transfers to interconnected regions via prion-like mechanisms and reaches the midbrain. General inflammation could promote α-syn accumulation and spread

Neuroinflammation May Promote Progression of Synucleinopathy from the Gastrointestinal Tract to the CNS

A growing body of evidence suggests that early on in PD, the peripheral nervous system and organs other than the brain are affected by neuropathological and neuroinflammatory events. Pathomechanisms in the ENS have raised interest in PD research due to distinct non-motor symptoms, such as dysphagia, constipation, and gastroesophageal reflux, experienced by PD patients [95, 157, 158, 159, 160, 161] and, interestingly, by certain elderly healthy individuals with no history of PD [96, 162, 163, 164]. Careful histological studies by Braak and colleagues support the hypothesis that accumulation of α-syn in the ENS could occur 20 years before the onset of degenerative changes in the CNS and associated motor symptoms [76, 94, 158, 164, 165]. The spread from the ENS to the CNS was proposed to occur via the DMV and the intermediolateral nucleus of the spinal cord [76, 166, 167]. Very little is known about the mechanisms that may promote this propagation. For example, a prion-like cell-to-cell progression along nerve bundles of the vagus nerve and spinal cord has been suggested [168, 169], which, similar to prion disorder, could involve immune pathways as well [170] (Fig. 2). This finds some clinical support in a study of patients with early stage diagnosed PD, where α-syn staining in the ENS correlated with compromised intestinal barrier integrity. Possible drivers of the observed pathology may have been bacterial and environmental toxins, resulting in increased oxidative stress most likely produced by macrophages in the luminal wall [97]. Yet in another study, patients with prolonged inflammation due to chronic inflammatory bowel disease did not display colonic synucleinopathy [171]. These findings in human patients indicate that acute local immune effects and certain forms of chronic intragastric inflammation may contribute differently to synucleinopathy in the GI.
Fig. 2

Possible spreading of synucleinopathy from the enteric nervous system to the brain. Macrophages in the lamina propria become reactive upon natural (e.g., bacteria, viruses, etc.) or induced (toxins) immune challenges. These cells react with secretion of inflammatory mediators (cytokines, chemokines, ROS, etc.), which can harm the surrounding tissue and may induce accumulation of α-syn in enteric nerves. This could alter gut activity, which early on may be observable by abnormal intestinal motility and constipation. Aggregated α-syn may be released by damaged nerve cells, which may further activate local macrophages. Cell-to-cell transmission could further contribute to the progression of synucleinopathy, which would eventually propagate from the enteric nervous system into the SNpc via nuclei in vagus and spinal cord

In order to model some of the putative mechanisms in vivo and to validate clinical observations, appropriate rodent models reflecting the symptoms found in possible early stage diagnosed PD were studied [172]. Some transgenic mice expressing mutant human α-syn encoded on artificial chromosomes reveal early aggregates of α-syn in the ENS and display motor deficits prior to detectable pathology in the CNS [172, 173]. In rats, intragastric injection of a selective proteasome inhibitor induced α-syn aggregation in DMV [174]. In other studies, chronic intragastric administration of the mitochondrial toxin rotenone to rats was reported to induce a progressive accumulation of endogenous α-syn starting in the ENS and reaching the brain along the vagal and spinal cord nerve connections to the substantia nigra [175]. Neuropathological changes in the toxicity-induced PD rat models were accompanied by local neuroinflammation. It can be assumed that the resulting tissue destruction and rotenone directly triggered a local immune activation and together this may have propagated the pathology from the GI system to the brain.

In support of a direct link between PD and gut immune status, it was found that the gene LRRK2, which is the major genetic cause for familial PD [176, 177, 178, 179, 180], is also located in a risk region for Crohn’s disease [181], an autoimmune-mediated chronic inflammatory bowel disease. In the brain, neuronal overexpression of LRRK2 accelerated the development of neuropathology in A53T α-syn transgenic mice, whereas its ablation suppresses neuronal aggregation and cytotoxicity of α-syn [182]. In the peripheral immune system, LRRK2 is upregulated in macrophages under inflammatory conditions which promotes the production of ROS, phagocytosis, and killing of bacteria [183]. The link between genetic risk for PD and GI immune mechanisms for LRRK2 is intriguing and warrants further studies to identify possible associations with progression of α-syn aggregation from the ENS to the brain.

Before doing so, a better understanding of the GI immune system is required. The intestines, and in particular the subepithelial lamina propria, contain the largest pool of tissue macrophages in humans. Thereby, the intestines share physiological similarities with the immune system of the olfactory epithelium. Macrophages in both locations demonstrate a two-edged sword: on one hand, they maintain tissue homeostasis by active phagocytosis of invading pathogens (e.g., bacteria, viruses) in the absence of excessive activation of other immune pathways [108, 166, 184]; on the other hand, they bear the potential to release an arsenal of detrimental cytokines, chemokines, and ROS [179, 180]. Thus, depending on the circumstances, GI macrophages have the potential to harm the surrounding tissue and may play a role in promoting the accumulation of α-syn in enteric nerves, leading to altered gut motility and constipation and, in later stages, to propagation of the pathology to the brain. If this indeed constitutes an etiological trigger in PD, then it could be relevant for developing earlier treatments and diagnosis of the disease.

Mechanisms of Cell-to-Cell Transfer

Post-mortem studies on PD patients who had received intrastriatal grafts of embryonic dopaminergic neurons over 10 years prior to death showed that some of the grafted neurons exhibit LBs and LNs cells [14, 16, 17, 185]. These findings stimulated the hypothesis that misfolded α-syn transferred directly from host brain cells to the grafted neurons. In support of this hypothesis, experiments performed in vitro [186, 187] and in vivo [13, 15, 188] have demonstrated that α-syn indeed can transfer between cells (Fig. 3) in a prion-like fashion. This is of direct relevance for how α-syn pathology might spread throughout the brain during the natural course of PD [12, 75, 168, 189]. For a comprehensive account of what is known about the underlying cellular and molecular mechanisms of cell-to-cell transfer of α-syn, we refer readers to other recent review articles on the topic [190, 191, 192] as it is beyond the scope of the current article. In brief, endocytosis [13, 193, 194] is strongly implicated as a α-syn uptake mechanism, and exosomes have been suggested to play a role when α-syn exits from cells. It has also been speculated that direct cell-to-cell transmission of α-syn occurs via tunneling nanotubes (tubes with a diameter <200 nm and containing F-actin) because a prior study demonstrated transfer of prion-protein via such structures [195]. Currently, the evidence linking α-syn misfolding or aggregation with cell-to-cell transfer is largely circumstantial. More studies are required to determine whether an increase of aggregated α-syn in a model system leads directly to an increase of the transfer rate of the protein. These studies are currently ongoing within our and other laboratories and should provide the evidence required to validate this hypothesis. Furthermore, the effects of neuroinflammation on the aforementioned cellular mechanisms are not known and inflammation might affect the rate of cell-to-cell α-syn transfer in either direction. For example, it is conceivable that some aspects of inflammation mitigates interneuronal α-syn transfer because activated microglia may phagocytose extracellular α-syn [44], thereby reducing the likelihood of neuron-to-neuron transfer of pathological α-syn. This hypothesis, however, remains to be tested. On the other hand, it has become clear that exposure of glial cells to α-syn or uptake of α-syn by astrocytes can turn their phenotype into a potentially more detrimental one for neurons [196, 197].
Fig. 3

α-Syn propagates from mouse brain to a graft of dopaminergic neurons. Confocal planes of a tyrosine hydroxylase-positive mouse neuron (green, a) transplanted in the striatum of a mouse overexpressing human α-syn. The arrowheads indicate the localization inside the grafted mouse cell of several human α-syn (red, b) dots, which have been transferred from the host brain. c An overlay of a and b. Scale bar 5 μm. Figure courtesy of Dr. Elodie Angot

Conclusions and Proposed Hypothesis

Although α-syn aggregation appears to be central to the development and progression of PD pathology, inflammation also plays an important role in this disease. Immune activation in the GI tract or in the olfactory system via chemical or virus exposure might trigger α-syn misfolding, subsequent aggregation, and propagation to the brain. It is also possible that neuroinflammation promotes the prion-like transfer of α-syn by increasing its release, increasing its uptake, or both. However, further studies are needed to support this hypothesis. If correct, it will open up new avenues for early detection and therapeutic intervention. For example, one could speculate that it will be possible to develop therapies which slow down the progression of PD by reducing the underlying inflammation and mitigating its effects on cell-to-cell α-syn transfer. In addition, it is conceivable that it would be possible to adopt a preventive strategy and lower the risk of developing PD by treating the triggers of inflammation in the olfactory or gastrointestinal system.



This work was supported by a European Research Council Advanced Grant, Swedish Research Council, Human Frontier Science Program, the Parkinson Foundation in Sweden, and ERA-Net NEURON–MIPROTRAN to Patrik Brundin and a Roche Postdoctoral Fellowship to Stefan Grathwohl. Patrik Brundin is a member of BAGADILICO Linnaeus environment and MultiPark strategic research area at Lund University, both of which are sponsored by the Swedish Research Council.

Open Access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


  1. 1.
    Fahn S (2003) Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14PubMedCrossRefGoogle Scholar
  2. 2.
    Chen X, de Silva HA, Pettenati MJ, Rao PN, St George-Hyslop P, Roses AD, Xia Y, Horsburgh K, Ueda K, Saitoh T (1995) The human NACP/alpha-synuclein gene: chromosome assignment to 4q21.3-q22 and TaqI RFLP analysis. Genomics 26:425–427PubMedCrossRefGoogle Scholar
  3. 3.
    Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815PubMedGoogle Scholar
  4. 4.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  5. 5.
    Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) Alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci U S A 95:6469–6473PubMedCrossRefGoogle Scholar
  6. 6.
    Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 251:205–208PubMedCrossRefGoogle Scholar
  7. 7.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  8. 8.
    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18:106–108PubMedCrossRefGoogle Scholar
  9. 9.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173PubMedCrossRefGoogle Scholar
  10. 10.
    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science 302:841PubMedCrossRefGoogle Scholar
  11. 11.
    Mata IF, Shi M, Agarwal P, Chung KA, Edwards KL, Factor SA, Galasko DR, Ginghina C, Griffith A, Higgins DS, Kay DM, Kim H, Leverenz JB, Quinn JF, Roberts JW, Samii A, Snapinn KW, Tsuang DW, Yearout D, Zhang J, Payami H, Zabetian CP (2010) SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol 67:1350–1356PubMedCrossRefGoogle Scholar
  12. 12.
    Brundin P, Li JY, Holton JL, Lindvall O, Revesz T (2008) Research in motion: the enigma of Parkinson's disease pathology spread. Nat Rev Neurosci 9:741–745PubMedCrossRefGoogle Scholar
  13. 13.
    Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P (2011) alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–725PubMedCrossRefGoogle Scholar
  14. 14.
    Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 14:504–506PubMedCrossRefGoogle Scholar
  15. 15.
    Kordower JH, Dodiya HB, Kordower AM, Terpstra B, Paumier K, Madhavan L, Sortwell C, Steece-Collier K, Collier TJ (2011) Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 43:552–557PubMedCrossRefGoogle Scholar
  16. 16.
    Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 14:501–503PubMedCrossRefGoogle Scholar
  17. 17.
    Kurowska Z, Englund E, Widnerd H, Lindvalle O, Lia J-Y, Brundin P (2011) Signs of degeneration in 12–22-year old grafts of mesencephalic dopamine neurons in patients with Parkinson's disease. J Park Dis 1:83–92Google Scholar
  18. 18.
    Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25PubMedCrossRefGoogle Scholar
  19. 19.
    Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110–122PubMedCrossRefGoogle Scholar
  20. 20.
    Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934PubMedCrossRefGoogle Scholar
  21. 21.
    Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 8:382–397PubMedCrossRefGoogle Scholar
  22. 22.
    Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W, Banati RB, Brooks DJ (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 21:404–412PubMedCrossRefGoogle Scholar
  23. 23.
    Ouchi Y, Yagi S, Yokokura M, Sakamoto M (2009) Neuroinflammation in the living brain of Parkinson's disease. Parkinsonism Relat Disord 15(Suppl 3):S200–204PubMedCrossRefGoogle Scholar
  24. 24.
    Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol 106:518–526PubMedCrossRefGoogle Scholar
  25. 25.
    McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38:1285–1291PubMedCrossRefGoogle Scholar
  26. 26.
    McGeer PL, Itagaki S, McGeer EG (1988) Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 76:550–557PubMedCrossRefGoogle Scholar
  27. 27.
    Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 52:1–6PubMedCrossRefGoogle Scholar
  28. 28.
    Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192PubMedGoogle Scholar
  29. 29.
    Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC (1994) Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease. Neurosci Lett 172:151–154PubMedCrossRefGoogle Scholar
  30. 30.
    Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett 202:17–20PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang J, Sokal I, Peskind ER, Quinn JF, Jankovic J, Kenney C, Chung KA, Millard SP, Nutt JG, Montine TJ (2008) CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol 129:526–529PubMedCrossRefGoogle Scholar
  32. 32.
    Vawter MP, Dillon-Carter O, Tourtellotte WW, Carvey P, Freed WJ (1996) TGFbeta1 and TGFbeta2 concentrations are elevated in Parkinson's disease in ventricular cerebrospinal fluid. Exp Neurol 142:313–322PubMedCrossRefGoogle Scholar
  33. 33.
    Shi M, Zhang J (2011) CSF alpha-synuclein, tau, and amyloid beta in Parkinson's disease. Lancet Neurol 10:681, author's reply 681-683PubMedCrossRefGoogle Scholar
  34. 34.
    Wang Y, Hancock AM, Bradner J, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Kim HM, Leverenz JB, Montine TJ, Ginghina C, Edwards KL, Snapinn KW, Goldstein DS, Shi M, Zhang J (2011) Complement 3 and factor h in human cerebrospinal fluid in Parkinson's disease, Alzheimer's disease, and multiple-system atrophy. Am J Pathol 178:1509–1516PubMedCrossRefGoogle Scholar
  35. 35.
    Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015PubMedGoogle Scholar
  36. 36.
    Steinman L (2008) Nuanced roles of cytokines in three major human brain disorders. J Clin Invest 118:3557–3563PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J 19:533–542PubMedCrossRefGoogle Scholar
  38. 38.
    Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T, Ciborowski P, Banerjee R, Gendelman HE (2008) Nitrated alpha-synuclein and microglial neuroregulatory activities. J Neuroimmune Pharmacol 3:59–74PubMedCrossRefGoogle Scholar
  39. 39.
    Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, Cerny R, Gelman B, Thomas MP, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein-activated microglial profiling for Parkinson's disease. J Neurochem 104:1504–1525PubMedCrossRefGoogle Scholar
  40. 40.
    Beraud D, Twomey M, Bloom B, Mittereder A, Ton V, Neitzke K, Chasovskikh S, Mhyre TR, Maguire-Zeiss KA (2011) alpha-Synuclein alters toll-like receptor expression. Front Neurosci 5:80PubMedCrossRefGoogle Scholar
  41. 41.
    Lee EJ, Woo MS, Moon PG, Baek MC, Choi IY, Kim WK, Junn E, Kim HS (2010) Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol 185:615–623PubMedCrossRefGoogle Scholar
  42. 42.
    Alvarez-Erviti L, Couch Y, Richardson J, Cooper JM, Wood MJ (2011) Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci Res 69:337–342PubMedCrossRefGoogle Scholar
  43. 43.
    Stefanova N, Fellner L, Reindl M, Masliah E, Poewe W, Wenning GK (2011) Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol 179:954–963PubMedCrossRefGoogle Scholar
  44. 44.
    Lee HJ, Suk JE, Bae EJ, Lee SJ (2008) Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun 372:423–428PubMedCrossRefGoogle Scholar
  45. 45.
    Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687–7698PubMedCrossRefGoogle Scholar
  46. 46.
    Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS (2011) Neuroinflammation and alpha-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson's disease. Environ Health Perspect 119:807–814PubMedCrossRefGoogle Scholar
  47. 47.
    Venda LL, Cragg SJ, Buchman VL, Wade-Martins R (2010) alpha-Synuclein and dopamine at the crossroads of Parkinson's disease. Trends Neurosci 33:559–568PubMedCrossRefGoogle Scholar
  48. 48.
    Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752PubMedCrossRefGoogle Scholar
  49. 49.
    Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164PubMedCrossRefGoogle Scholar
  50. 50.
    Paleologou KE, Oueslati A, Shakked G, Rospigliosi CC, Kim HY, Lamberto GR, Fernandez CO, Schmid A, Chegini F, Gai WP, Chiappe D, Moniatte M, Schneider BL, Aebischer P, Eliezer D, Zweckstetter M, Masliah E, Lashuel HA (2010) Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 30:3184–3198PubMedCrossRefGoogle Scholar
  51. 51.
    Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H, McGeer EG, McGeer PL (2008) Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol Aging 29:739–752PubMedCrossRefGoogle Scholar
  52. 52.
    Azeredo da Silveira S, Schneider BL, Cifuentes-Diaz C, Sage D, Abbas-Terki T, Iwatsubo T, Unser M, Aebischer P (2009) Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson's disease. Hum Mol Genet 18:872–887PubMedGoogle Scholar
  53. 53.
    Sato H, Arawaka S, Hara S, Fukushima S, Koga K, Koyama S, Kato T (2011) Authentically phosphorylated alpha-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson's disease. J Neurosci 31:16884–16894PubMedCrossRefGoogle Scholar
  54. 54.
    Lee KW, Chen W, Junn E, Im JY, Grosso H, Sonsalla PK, Feng X, Ray N, Fernandez JR, Chao Y, Masliah E, Voronkov M, Braithwaite SP, Stock JB, Mouradian MM (2011) Enhanced phosphatase activity attenuates alpha-synucleinopathy in a mouse model. J Neurosci 31:6963–6971PubMedCrossRefGoogle Scholar
  55. 55.
    Oueslati A, Paleologou KE, Schneider BL, Aebischer P, Lashuel HA (2012) Mimicking phosphorylation at serine 87 inhibits the aggregation of human alpha-synuclein and protects against its toxicity in a rat model of Parkinson's disease. J Neurosci 32:1536–1544PubMedCrossRefGoogle Scholar
  56. 56.
    Duda JE, Giasson BI, Chen Q, Gur TL, Hurtig HI, Stern MB, Gollomp SM, Ischiropoulos H, Lee VM, Trojanowski JQ (2000) Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am J Pathol 157:1439–1445PubMedCrossRefGoogle Scholar
  57. 57.
    Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376PubMedCrossRefGoogle Scholar
  58. 58.
    Gao H-M, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VMY (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687–7698PubMedCrossRefGoogle Scholar
  59. 59.
    Khandelwal PJ, Dumanis SB, Herman AM, Rebeck GW, Moussa CE (2012) Wild type and P301L mutant Tau promote neuro-inflammation and alpha-Synuclein accumulation in lentiviral gene delivery models. Mol Cell Neurosci 49:44–53PubMedCrossRefGoogle Scholar
  60. 60.
    Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 90:11282–11286PubMedCrossRefGoogle Scholar
  61. 61.
    Ishikawa A, Piao YS, Miyashita A, Kuwano R, Onodera O, Ohtake H, Suzuki M, Nishizawa M, Takahashi H (2005) A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol 57:429–434PubMedCrossRefGoogle Scholar
  62. 62.
    Snider BJ, Norton J, Coats MA, Chakraverty S, Hou CE, Jervis R, Lendon CL, Goate AM, McKeel DW Jr, Morris JC (2005) Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol 62:1821–1830PubMedCrossRefGoogle Scholar
  63. 63.
    Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ, Samali A (2011) Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med 15:2025–2039PubMedCrossRefGoogle Scholar
  64. 64.
    Gundersen V (2010) Protein aggregation in Parkinson's disease. Acta Neurol Scand Suppl 190:82-87Google Scholar
  65. 65.
    Myohanen TT, Hannula MJ, Van Elzen R, Gerard M, Van Der Veken P, Garcia-Horsman JA, Baekelandt V, Mannisto PT, Lambeir AM (2012) A prolyl oligopeptidase inhibitor, KYP-2047, reduces alpha-synuclein protein levels and aggregates in cellular and animal models of Parkinson's disease. Br J Pharmacol. doi: 10.1111/j.1476-5381.2012.01846.x
  66. 66.
    Schapira AH, Gegg M (2011) Mitochondrial contribution to Parkinson's disease pathogenesis. Parkinsons Dis 2011:159160PubMedGoogle Scholar
  67. 67.
    Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P (2009) Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int J Biochem Cell Biol 41:2015–2024PubMedCrossRefGoogle Scholar
  68. 68.
    Galli M, Van Gool F, Leo O (2011) Sirtuins and inflammation: friends or foes? Biochem Pharmacol 81:569–576PubMedCrossRefGoogle Scholar
  69. 69.
    Donmez G, Arun A, Chung CY, McLean PJ, Lindquist S, Guarente L (2012) SIRT1 protects against α-synuclein aggregation by activating molecular chaperones. J Neurosci 32:124–132PubMedCrossRefGoogle Scholar
  70. 70.
    Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250PubMedCrossRefGoogle Scholar
  71. 71.
    Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59PubMedCrossRefGoogle Scholar
  72. 72.
    Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89PubMedCrossRefGoogle Scholar
  73. 73.
    Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J Neurol 249(Suppl 3):III/1–5Google Scholar
  74. 74.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  75. 75.
    Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536PubMedCrossRefGoogle Scholar
  76. 76.
    Hawkes CH, Del Tredici K, Braak H (2010) A timeline for Parkinson's disease. Parkinsonism Relat Disord 16:79–84PubMedCrossRefGoogle Scholar
  77. 77.
    Wakabayashi K, Kawachi I, Toyoshima Y, Takahashi H (1999) [Occurrence of argyrophilic grains in multiple system atrophy: histopathological examination of 26 autopsy cases]. No to shinkei =. Brain and nerve 51:433–437PubMedGoogle Scholar
  78. 78.
    Cersosimo MG, Perandones C, Micheli FE, Raina GB, Beron AM, Nasswetter G, Radrizzani M, Benarroch EE (2011) Alpha-synuclein immunoreactivity in minor salivary gland biopsies of Parkinson's disease patients. Mov Dis: Off J Mov Dis Soc 26:188–190CrossRefGoogle Scholar
  79. 79.
    Hawkes CH, Del Tredici K, Braak H (2009) Parkinson's disease: the dual hit theory revisited. Ann N Y Acad Sci 1170:615–622PubMedCrossRefGoogle Scholar
  80. 80.
    Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of alpha-synuclein staging. Neuropathol Appl Neurobiol 34:284–295PubMedCrossRefGoogle Scholar
  81. 81.
    Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG (2008) Patterns and stages of alpha-synucleinopathy: relevance in a population-based cohort. Neurology 70:1042–1048PubMedCrossRefGoogle Scholar
  82. 82.
    Attems J, Jellinger KA (2008) The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease. Neuropathol Appl Neurobiol 34:466–467PubMedCrossRefGoogle Scholar
  83. 83.
    Parkkinen L, Pirttila T, Alafuzoff I (2008) Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol 115:399–407PubMedCrossRefGoogle Scholar
  84. 84.
    Brooks DJ (2010) Examining Braak's hypothesis by imaging Parkinson's disease. Mov Disord 25(Suppl 1):S83–88PubMedCrossRefGoogle Scholar
  85. 85.
    Jellinger KA (2010) Critical evaluation of the Braak staging scheme for Parkinson's disease. Ann Neurol 67:550PubMedCrossRefGoogle Scholar
  86. 86.
    Linazasoro G (2007) Classical Parkinson disease versus Parkinson complex—reflections against staging and in favour of heterogeneity. Eur J Neurol 14:721–728PubMedCrossRefGoogle Scholar
  87. 87.
    Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I, Bogdanovic N, Bugiani O, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovacs GG, Meyronet D, Monoranu C, Parchi P, Parkkinen L, Patsouris E, Roggendorf W, Rozemuller A, Stadelmann-Nessler C, Streichenberger N, Thal DR, Kretzschmar H (2009) Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:635–652PubMedCrossRefGoogle Scholar
  88. 88.
    Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, White CL 3rd, Akiyama H, Caviness J, Shill HA, Connor DJ, Sabbagh MN, Walker DG (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634PubMedCrossRefGoogle Scholar
  89. 89.
    Bassetti CL (2011) Nonmotor disturbances in Parkinson´s disease. Neurodegener Dis 8:95–108PubMedCrossRefGoogle Scholar
  90. 90.
    Doty RL (2007) Olfaction in Parkinson's disease. Parkinsonism Relat Disord 13(Suppl 3):S225–228PubMedCrossRefGoogle Scholar
  91. 91.
    Morley JF, Duda JE (2010) Olfaction as a biomarker in Parkinson's disease. Biomark Med 4:661–670PubMedCrossRefGoogle Scholar
  92. 92.
    Doty RL (ed) (2003) Handbook of olfaction and gustation. Marcel Dekker, New YorkGoogle Scholar
  93. 93.
    Hawkes CH, Shephard BC, Daniel SE (1999) Is Parkinson's disease a primary olfactory disorder? QJM 92:473–480PubMedCrossRefGoogle Scholar
  94. 94.
    Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW (2001) Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 57:456–462PubMedCrossRefGoogle Scholar
  95. 95.
    Lebouvier T, Neunlist M, Bruley des Varannes S, Coron E, Drouard A, N'Guyen JM, Chaumette T, Tasselli M, Paillusson S, Flamand M, Galmiche JP, Damier P, Derkinderen P (2010) Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PLoS One 5:e12728PubMedCrossRefGoogle Scholar
  96. 96.
    Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, Ortega-Moreno A, Rebollo AC, Gomez-Rio M, Concha A, Munoz DG (2007) Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders?: a cohort study. Neurology 68:2012–2018PubMedCrossRefGoogle Scholar
  97. 97.
    Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A (2011) Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease. PLoS One 6:e28032PubMedCrossRefGoogle Scholar
  98. 98.
    Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702PubMedCrossRefGoogle Scholar
  99. 99.
    Hawkes CH, Del Tredici K, Braak H (2007) Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614PubMedCrossRefGoogle Scholar
  100. 100.
    Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426PubMedGoogle Scholar
  101. 101.
    Vroon A, Drukarch B, Bol JG, Cras P, Breve JJ, Allan SM, Relton JK, Hoogland PV, Van Dam AM (2007) Neuroinflammation in Parkinson's patients and MPTP-treated mice is not restricted to the nigrostriatal system: microgliosis and differential expression of interleukin-1 receptors in the olfactory bulb. Exp Gerontol 42:762–771PubMedCrossRefGoogle Scholar
  102. 102.
    Bang FB (1961) Mucociliary function as protective mechanism in upper respiratory tract. Bacteriol Rev 25:228–236PubMedGoogle Scholar
  103. 103.
    Watelet JB, Strolin-Benedetti M, Whomsley R (2009) Defence mechanisms of olfactory neuro-epithelium: mucosa regeneration, metabolising enzymes and transporters. B-ENT 5(Suppl 13):21–37PubMedGoogle Scholar
  104. 104.
    Genter MB, Kendig EL, Knutson MD (2009) Uptake of materials from the nasal cavity into the blood and brain: are we finally beginning to understand these processes at the molecular level? Ann N Y Acad Sci 1170:623–628PubMedCrossRefGoogle Scholar
  105. 105.
    Kovacs T (2004) Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders. Ageing Res Rev 3:215–232PubMedCrossRefGoogle Scholar
  106. 106.
    Ache BW, Young JM (2005) Olfaction: diverse species, conserved principles. Neuron 48:417–430PubMedCrossRefGoogle Scholar
  107. 107.
    Wu CH, Wang HJ, Wen CY, Lien KC, Ling EA (1997) Response of amoeboid and ramified microglial cells to lipopolysaccharide injections in postnatal rats—a lectin and ultrastructural study. Neurosci Res 27:133–141PubMedCrossRefGoogle Scholar
  108. 108.
    Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170PubMedCrossRefGoogle Scholar
  109. 109.
    Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31:16064–16069PubMedCrossRefGoogle Scholar
  110. 110.
    Caggiano AO, Brunjes PC (1993) Microglia and the developing olfactory bulb. Neuroscience 52:717–724PubMedCrossRefGoogle Scholar
  111. 111.
    Crews L, Hunter D (1994) Neurogenesis in the olfactory epithelium. Perspect Dev Neurobiol 2:151–161PubMedGoogle Scholar
  112. 112.
    Curtis MA, Kam M, Faull RL (2011) Neurogenesis in humans. Eur J Neurosci 33:1170–1174PubMedCrossRefGoogle Scholar
  113. 113.
    Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702PubMedCrossRefGoogle Scholar
  114. 114.
    Loseva E, Yuan TF, Karnup S (2009) Neurogliogenesis in the mature olfactory system: a possible protective role against infection and toxic dust. Brain Res Rev 59:374–387PubMedCrossRefGoogle Scholar
  115. 115.
    Kalinke U, Bechmann I, Detje CN (2011) Host strategies against virus entry via the olfactory system. Virulence 2:367–370PubMedCrossRefGoogle Scholar
  116. 116.
    Abdulwahid Arif I, Ahmad Khan H (2010) Environmental toxins and Parkinson's disease: putative roles of impaired electron transport chain and oxidative stress. Toxicol Ind Health 26:121–128PubMedCrossRefGoogle Scholar
  117. 117.
    Hodgson NR, Bohnet SG, Majde JA, Krueger JM (2012) Influenza virus pathophysiology and brain invasion in mice with functional and dysfunctional Mx1 genes. Brain Behav Immun 26:83–89PubMedCrossRefGoogle Scholar
  118. 118.
    Islam Z, Amuzie CJ, Harkema JR, Pestka JJ (2007) Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene mycotoxin roridin a: kinetics and potentiation by bacterial lipopolysaccharide coexposure. Toxicol Sci 98:526–541PubMedCrossRefGoogle Scholar
  119. 119.
    Majde JA (2010) Neuroinflammation resulting from covert brain invasion by common viruses—a potential role in local and global neurodegeneration. Med Hypotheses 75:204–213PubMedCrossRefGoogle Scholar
  120. 120.
    Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C (2004) Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 16:437–445PubMedCrossRefGoogle Scholar
  121. 121.
    Simko M, Mattsson MO (2010) Risks from accidental exposures to engineered nanoparticles and neurological health effects: a critical review. Part Fibre Toxicol 7:42PubMedCrossRefGoogle Scholar
  122. 122.
    Mattock C, Marmot M, Stern G (1988) Could Parkinson's disease follow intra-uterine influenza?: a speculative hypothesis. J Neurol Neurosurg Psychiatry 51:753–756PubMedCrossRefGoogle Scholar
  123. 123.
    Martyn CN (1997) Infection in childhood and neurological diseases in adult life. Br Med Bull 53:24–39PubMedCrossRefGoogle Scholar
  124. 124.
    Bower JH, Maraganore DM, Peterson BJ, Ahlskog JE, Rocca WA (2006) Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case–control study. Neurology 67:494–496PubMedCrossRefGoogle Scholar
  125. 125.
    Rohn TT, Catlin LW (2011) Immunolocalization of influenza A virus and markers of inflammation in the human Parkinson's disease brain. PLoS One 6:e20495PubMedCrossRefGoogle Scholar
  126. 126.
    Yamada T (1996) Viral etiology of Parkinson's disease: focus on influenza A virus. Parkinsonism Relat Disord 2:113–121PubMedCrossRefGoogle Scholar
  127. 127.
    El-Habashi N, El-Nahass el S, Fukushi H, Hibi D, Sakai H, Sasseville V, Yanai T (2010) Experimental intranasal infection of equine herpesvirus 9 (EHV-9) in suckling hamsters: kinetics of viral transmission and inflammation in the nasal cavity and brain. J Neurovirol 16:242–248PubMedCrossRefGoogle Scholar
  128. 128.
    Leyva-Grado VH, Churchill L, Wu M, Williams TJ, Taishi P, Majde JA, Krueger JM (2009) Influenza virus- and cytokine-immunoreactive cells in the murine olfactory and central autonomic nervous systems before and after illness onset. J Neuroimmunol 211:73–83PubMedCrossRefGoogle Scholar
  129. 129.
    Aronsson F, Robertson B, Ljunggren HG, Kristensson K (2003) Invasion and persistence of the neuroadapted influenza virus A/WSN/33 in the mouse olfactory system. Viral Immunol 16:415–423PubMedCrossRefGoogle Scholar
  130. 130.
    Armien AG, Hu S, Little MR, Robinson N, Lokensgard JR, Low WC, Cheeran MC (2010) Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis. Brain Pathol 20:738–750PubMedCrossRefGoogle Scholar
  131. 131.
    Shankar V, Kao M, Hamir AN, Sheng H, Koprowski H, Dietzschold B (1992) Kinetics of virus spread and changes in levels of several cytokine mRNAs in the brain after intranasal infection of rats with Borna disease virus. J Virol 66:992–998PubMedGoogle Scholar
  132. 132.
    Detje CN, Meyer T, Schmidt H, Kreuz D, Rose JK, Bechmann I, Prinz M, Kalinke U (2009) Local type I IFN receptor signaling protects against virus spread within the central nervous system. J Immunol 182:2297–2304PubMedCrossRefGoogle Scholar
  133. 133.
    Majde JA, Bohnet SG, Ellis GA, Churchill L, Leyva-Grado V, Wu M, Szentirmai E, Rehman A, Krueger JM (2007) Detection of mouse-adapted human influenza virus in the olfactory bulbs of mice within hours after intranasal infection. J Neurovirol 13:399–409PubMedCrossRefGoogle Scholar
  134. 134.
    Kim C, Lee SJ (2008) Controlling the mass action of alpha-synuclein in Parkinson's disease. J Neurochem 107:303–316PubMedCrossRefGoogle Scholar
  135. 135.
    Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med 38:333–347PubMedCrossRefGoogle Scholar
  136. 136.
    Winkler F, Koedel U, Kastenbauer S, Pfister HW (2001) Differential expression of nitric oxide synthases in bacterial meningitis: role of the inducible isoform for blood–brain barrier breakdown. J Infect Dis 183:1749–1759PubMedCrossRefGoogle Scholar
  137. 137.
    Rhodin J, Thomas T, Bryant M, Clark L, Sutton ET (1999) Animal model of vascular inflammation. J Submicrosc Cytol Pathol 31:305–311PubMedGoogle Scholar
  138. 138.
    Dvorska I, Brust P, Hrbas P, Ruhle HJ, Barth T, Ermisch A (1992) On the blood–brain barrier to peptides: effects of immobilization stress on regional blood supply and accumulation of labelled peptides in the rat brain. Endocr Regul 26:77–82PubMedGoogle Scholar
  139. 139.
    Ermisch A (1992) Peptide receptors of the blood–brain barrier and substrate transport into the brain. Prog Brain Res 91:155–161PubMedCrossRefGoogle Scholar
  140. 140.
    Nonaka N, Farr SA, Kageyama H, Shioda S, Banks WA (2008) Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins. J Pharmacol Exp Ther 325:513–519PubMedCrossRefGoogle Scholar
  141. 141.
    Yamada K, Hasegawa M, Kametani S, Ito S (2007) Nose-to-brain delivery of TS-002, prostaglandin D2 analogue. J Drug Target 15:59–66PubMedCrossRefGoogle Scholar
  142. 142.
    Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA (2004) Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10:1366–1373PubMedCrossRefGoogle Scholar
  143. 143.
    Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A 106:14063–14068PubMedCrossRefGoogle Scholar
  144. 144.
    Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: an X-ray microanalysis. J Neurochem 56:446–451PubMedCrossRefGoogle Scholar
  145. 145.
    Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2009) Dietary fats, cholesterol and iron as risk factors for Parkinson's disease. Parkinsonism Relat Disord 15:47–52PubMedCrossRefGoogle Scholar
  146. 146.
    Oberdorster G, Oberdorster E, Oberdorster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823–839PubMedCrossRefGoogle Scholar
  147. 147.
    Calderon-Garciduenas L, Maronpot RR, Torres-Jardon R, Henriquez-Roldan C, Schoonhoven R, Acuna-Ayala H, Villarreal-Calderon A, Nakamura J, Fernando R, Reed W, Azzarelli B, Swenberg JA (2003) DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration. Toxicol Pathol 31:524–538PubMedCrossRefGoogle Scholar
  148. 148.
    Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdorster G (2006) Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 114:1172–1178PubMedCrossRefGoogle Scholar
  149. 149.
    Garcia GJ, Kimbell JS (2009) Deposition of inhaled nanoparticles in the rat nasal passages: dose to the olfactory region. Inhal Toxicol 21:1165–1175PubMedCrossRefGoogle Scholar
  150. 150.
    Tin Tin Win S, Mitsushima D, Yamamoto S, Fukushima A, Funabashi T, Kobayashi T, Fujimaki H (2008) Changes in neurotransmitter levels and proinflammatory cytokine mRNA expressions in the mice olfactory bulb following nanoparticle exposure. Toxicol Appl Pharmacol 226:192–198CrossRefGoogle Scholar
  151. 151.
    Wang Y, Wang B, Zhu MT, Li M, Wang HJ, Wang M, Ouyang H, Chai ZF, Feng WY, Zhao YL (2011) Microglial activation, recruitment and phagocytosis as linked phenomena in ferric oxide nanoparticle exposure. Toxicol Lett 205:26–37PubMedCrossRefGoogle Scholar
  152. 152.
    Prediger RD, Aguiar AS Jr, Matheus FC, Walz R, Antoury L, Raisman-Vozari R, Doty RL (2012) Intranasal administration of neurotoxicants in animals: support for the olfactory vector hypothesis of Parkinson's disease. Neurotox Res 21:90–116PubMedCrossRefGoogle Scholar
  153. 153.
    Mori K, Kaneko YS, Nakashima A, Nagatsu I, Takahashi H, Ota A (2005) Peripheral lipopolysaccharide induces apoptosis in the murine olfactory bulb. Brain Res 1039:116–129PubMedCrossRefGoogle Scholar
  154. 154.
    Ota A, Mori K, Kaneko YS, Nakashima A, Nagatsu I, Nagatsu T (2008) Peripheral lipopolysaccharide administration affects the olfactory dopamine system in mice. Ann N Y Acad Sci 1148:127–135PubMedCrossRefGoogle Scholar
  155. 155.
    Sultan B, May LA, Lane AP (2011) The role of TNF-alpha in inflammatory olfactory loss. Laryngoscope 121:2481–2486PubMedCrossRefGoogle Scholar
  156. 156.
    Turner JH, Liang KL, May L, Lane AP (2010) Tumor necrosis factor alpha inhibits olfactory regeneration in a transgenic model of chronic rhinosinusitis-associated olfactory loss. Am J Rhinol Allergy 24:336–340PubMedCrossRefGoogle Scholar
  157. 157.
    Cersosimo MG, Perandones C, Micheli FE, Raina GB, Beron AM, Nasswetter G, Radrizzani M, Benarroch EE (2011) Alpha-synuclein immunoreactivity in minor salivary gland biopsies of Parkinson's disease patients. Mov Disord 26:188–190PubMedCrossRefGoogle Scholar
  158. 158.
    Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 396:67–72PubMedCrossRefGoogle Scholar
  159. 159.
    Edwards LL, Quigley EM, Pfeiffer RF (1992) Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology. Neurology 42:726–732PubMedCrossRefGoogle Scholar
  160. 160.
    Lebouvier T, Chaumette T, Damier P, Coron E, Touchefeu Y, Vrignaud S, Naveilhan P, Galmiche JP, Bruley des Varannes S, Derkinderen P, Neunlist M (2008) Pathological lesions in colonic biopsies during Parkinson's disease. Gut 57:1741–1743PubMedCrossRefGoogle Scholar
  161. 161.
    Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H (2010) Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease. Acta Neuropathol 119:703–713PubMedCrossRefGoogle Scholar
  162. 162.
    Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 32:284–295PubMedCrossRefGoogle Scholar
  163. 163.
    Probst A, Bloch A, Tolnay M (2008) New insights into the pathology of Parkinson's disease: does the peripheral autonomic system become central? Eur J Neurol: The Off J Eur Fed Neurol Soc 15(Suppl 1):1–4Google Scholar
  164. 164.
    Schapira AH, Tolosa E (2010) Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat Rev Neurol 6:309–317PubMedCrossRefGoogle Scholar
  165. 165.
    Ueki A, Otsuka M (2004) Life style risks of Parkinson's disease: association between decreased water intake and constipation. J Neurol 251(Suppl 7):vII18–23PubMedCrossRefGoogle Scholar
  166. 166.
    Wakabayashi K, Toyoshima Y, Awamori K, Anezaki T, Yoshimoto M, Tsuji S, Takahashi H (1999) Restricted occurrence of Lewy bodies in the dorsal vagal nucleus in a patient with late-onset parkinsonism. J Neurol Sci 165:188–191PubMedCrossRefGoogle Scholar
  167. 167.
    Cersosimo MG, Benarroch EE (2011) Pathological correlates of gastrointestinal dysfunction in Parkinson's disease. Neurobiol Dis. doi: 10.1016/j.nbd.2011.10.014
  168. 168.
    Angot E, Steiner JA, Hansen C, Li JY, Brundin P (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9:1128–1138PubMedCrossRefGoogle Scholar
  169. 169.
    Cicchetti F, Drouin-Ouellet J, Gross RE (2009) Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci 30:475–483PubMedCrossRefGoogle Scholar
  170. 170.
    Aguzzi A, Heppner FL, Heikenwalder M, Prinz M, Mertz K, Seeger H, Glatzel M (2003) Immune system and peripheral nerves in propagation of prions to CNS. Br Med Bull 66:141–159PubMedCrossRefGoogle Scholar
  171. 171.
    Shannon KM, Keshavarzian A, Mutlu E, Dodiya HB, Daian D, Jaglin JA, Kordower JH (2011) Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease. Mov Dis: Off J Mov Dis Soc. doi: 10.1002/mds.23838
  172. 172.
    Greene JG (2011) Animal models of gastrointestinal problems in Parkinson's disease. J Park Dis 1:137–149Google Scholar
  173. 173.
    Kuo YM, Li Z, Jiao Y, Gaborit N, Pani AK, Orrison BM, Bruneau BG, Giasson BI, Smeyne RJ, Gershon MD, Nussbaum RL (2010) Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes. Hum Mol Genet 19:1633–1650PubMedCrossRefGoogle Scholar
  174. 174.
    Miwa H, Kubo T, Suzuki A, Kondo T (2006) Intragastric proteasome inhibition induces alpha-synuclein-immunopositive aggregations in neurons in the dorsal motor nucleus of the vagus in rats. Neurosci Lett 401:146–149PubMedCrossRefGoogle Scholar
  175. 175.
    Pan-Montojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R, Jackson S, Gille G, Spillantini MG, Reichmann H, Funk RH (2010) Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One 5:e8762PubMedCrossRefGoogle Scholar
  176. 176.
    Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:595–600PubMedCrossRefGoogle Scholar
  177. 177.
    Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607PubMedCrossRefGoogle Scholar
  178. 178.
    Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C (2009) The genetics of Parkinson's syndromes: a critical review. Curr Opin Genet Dev 19:254–265PubMedCrossRefGoogle Scholar
  179. 179.
    Kahle PJ, Waak J, Gasser T (2009) DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders. Free Radic Biol Med 47:1354–1361PubMedCrossRefGoogle Scholar
  180. 180.
    McGeer PL, McGeer EG (2008) Glial reactions in Parkinson's disease. Mov Disord 23:474–483PubMedCrossRefGoogle Scholar
  181. 181.
    Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40:955–962PubMedCrossRefGoogle Scholar
  182. 182.
    Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun L, Xie C, Long CX, Yang WJ, Ding J, Chen ZZ, Gallant PE, Tao-Cheng JH, Rudow G, Troncoso JC, Liu Z, Li Z, Cai H (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64:807–827PubMedCrossRefGoogle Scholar
  183. 183.
    Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C, Korzenik JR, Rioux JD, Daly MJ, Xavier RJ, Podolsky DK (2010) LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol 185:5577–5585PubMedCrossRefGoogle Scholar
  184. 184.
    Weber B, Saurer L, Mueller C (2009) Intestinal macrophages: differentiation and involvement in intestinal immunopathologies. Semin Immunopathol 31:171–184PubMedCrossRefGoogle Scholar
  185. 185.
    Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB (2008) Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord 23:2303–2306PubMedCrossRefGoogle Scholar
  186. 186.
    Luk KC, Song C, O'Brien P, Stieber A, Branch JR, Brunden KR, Trojanowski JQ, Lee VM (2009) Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A 106:20051–20056PubMedGoogle Scholar
  187. 187.
    Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 106:13010–13015PubMedCrossRefGoogle Scholar
  188. 188.
    Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchere J, Lakhdar L, Legastelois S, Baron T (2012) Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2011.06.022
  189. 189.
    Lerner A, Bagic A (2008) Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord 23:1076–1084PubMedCrossRefGoogle Scholar
  190. 190.
    Dunning CJ, Reyes JF, Steiner JA, Brundin P (2012) Can Parkinson's disease pathology be propagated from one neuron to another? Prog Neurobiol. doi: 10.1016/j.pneurobio.2011.11.003
  191. 191.
    Steiner JA, Angot E, Brundin P (2011) A deadly spread: cellular mechanisms of alpha-synuclein transfer. Cell Death Differ 18:1425–1433PubMedCrossRefGoogle Scholar
  192. 192.
    Lee SJ, Desplats P, Sigurdson C, Tsigelny I, Masliah E (2010) Cell-to-cell transmission of non-prion protein aggregates. Nat Rev Neurol 6:702–706PubMedCrossRefGoogle Scholar
  193. 193.
    Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, Meaney DF, Trojanowski JQ, Lee VM (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71PubMedCrossRefGoogle Scholar
  194. 194.
    Lee HJ, Suk JE, Bae EJ, Lee JH, Paik SR, Lee SJ (2008) Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol 40:1835–1849PubMedCrossRefGoogle Scholar
  195. 195.
    Gousset K, Schiff E, Langevin C, Marijanovic Z, Caputo A, Browman DT, Chenouard N, de Chaumont F, Martino A, Enninga J, Olivo-Marin JC, Mannel D, Zurzolo C (2009) Prions hijack tunnelling nanotubes for intercellular spread. Nat Cell Biol 11:328–336PubMedCrossRefGoogle Scholar
  196. 196.
    Koob AO, Paulino AD, Masliah E (2010) GFAP reactivity, apolipoprotein E redistribution and cholesterol reduction in human astrocytes treated with alpha-synuclein. Neurosci Lett 469:11–14PubMedCrossRefGoogle Scholar
  197. 197.
    Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • Carla M. Lema Tomé
    • 1
    Email author
  • Trevor Tyson
    • 1
  • Nolwen L. Rey
    • 1
  • Stefan Grathwohl
    • 2
  • Markus Britschgi
    • 2
  • Patrik Brundin
    • 1
    • 3
    Email author
  1. 1.Neuronal Survival Unit, Wallenberg Neuroscience CenterLund UniversityLundSweden
  2. 2.F. Hoffmann-La Roche Ltd, pRED, Pharma Research & Early Development, DTA CNSBaselSwitzerland
  3. 3.Center for Neurodegenerative ScienceVan Andel Research InstituteGrand RapidsUSA

Personalised recommendations