Complicity of α-synuclein oligomer and calcium dyshomeostasis in selective neuronal vulnerability in Lewy body disease

α-Synuclein oligomers and Ca2+ dyshomeostasis have been thoroughly investigated with respect to the pathogenesis of Lewy body disease (LBD). In LBD, α-synuclein oligomers exhibit a neuron-specific cytoplasmic distribution. Highly active neurons and neurons with a high Ca2+ burden are prone to damage in LBD. The neuronal vulnerability may be determined by transneuronal axonal transmission of the pathological processes; however, this hypothesis seems inconsistent with pathological findings that neurons anatomically connected to LBD-vulnerable neurons, such as neurons in the ventral tegmentum, are spared in LBD. This review focuses on and discusses the crucial roles played by α-synuclein oligomers and Ca2+ dyshomeostasis in early intraneural pathophysiology in LBD-vulnerable neurons. A challenging view is proposed on the synergy between retrograde transport of α-synuclein and vesicular Ca release, whereby neuronal vulnerability is propagated backward along repeatedly activated signaling pathway.


Introduction
The pathological hallmarks of Lewy body disease (LBD), [also known as Parkinson's disease (PD) and dementia with Tredici and Braak 2020), what is the basis of selective neuronal fragility in LBD?
This review focuses on two key features of neurons in the LBD brain that contribute to the pathophysiology of LBD-vulnerable neurons: α-synuclein oligomers and calcium dyshomeostasis. Also discussed is the recent finding that α-synuclein oligomers trigger an aberrant form of robust-firing-induced calcium release from the endoplasmic reticulum (ER), which is mediated by direct binding with calcium binding protein 1 (CaBP1), a neuron-specific member of the calmodulin superfamily. This binding disrupts the normal Ca 2+ -and IP 3 -dependent regulation of inositol 1, 4, 5-trisphosphate (IP 3 ) receptors (IP 3 Rs) (Yamamoto et al. 2019). The present review proposes that this signaling-pathspecific calcium dysregulation uniquely contributes to early oligomeric α-synuclein-mediated pathophysiology in LBDvulnerable neurons.

α-Synuclein oligomers: a pivotal factor in LBD pathogenesis
α-Synuclein is highly expressed in the brain and is enriched at presynaptic terminals. It augments assembly of the SNARE machinery, and plays a role in neurotransmitter release and protection of nerve terminals against injury (Kalia et al. 2013). The main physiological form of α-synuclein in the brain appears to be an unfolded monomer, but it also forms soluble oligomeric species that are toxic to neurons (Irvine et al. 2008;Dehay et al. 2015;Ingelsson 2016). The presence of α-synuclein oligomers has been demonstrated not only with recombinant proteins or in cell culture and in vivo models, but also in post-mortem brain tissue from LBD patients (Cappai et al. 2005;Yamakawa et al. 2010;Sharon et al. 2003;Paleologou et al. 2009). Proximity ligation assays of LBD brain tissue can detect α-synuclein oligomers, which can go undetected by conventional immunohistochemistry using anti-α-synuclein antibodies (Roberts et al. 2015). α-Synuclein oligomers can be observed not only in the neuropil, but also in the cytosol of LBD-vulnerable neurons, which can precede the development of classical PD lesions, such as pale bodies or Lewy bodies. (Roberts et al. 2015).

Dysregulated Ca 2+ homeostasis: a key feature of selective neuronal fragility in LBD
Dysregulation of Ca 2+ homeostasis is a core pathological mechanism in LBD. It triggers the formation of α-synuclein oligomers, mitochondrial and ER stress, and inhibition of autophagy and lysosomal pathways, thereby leading to neurodegeneration (Surmeier and Sulzer 2013). In SNc neurons of aging mice, Ca 2+ entry via CaV1.3, an L-type voltage-dependent Ca 2+ channel (VDCC) during autonomous action potentials causes oxidative stress and cell damage (Chan et al. 2007;Surmeier and Sulzer 2013). Epidemiological studies indicate that L-type VDCC (L-VDCC) blockers diminish the risk of PD (Ritz et al. 2010;Ascherio and Schwarzschild 2016). Moreover, soluble oligomeric α-synuclein induces Ca 2+ influx and seeding (Danzer et al. 2007), and promotes Ca 2+ -induced mitochondrial dysfunction (Luth et al. 2014). Taken together, these observations raise the possibility that the close relationship between α-synuclein oligomers and the dysregulation of intracellular Ca 2+ handling by intraneural organelles may play a central role in LBD pathogenesis.
In general, LBD-vulnerable neurons, such as neurons in the SNc, the locus coeruleus, the raphe nuclei and the nucleus basalis of Meynert, have a common physiological phenotype; an autonomous pacemaker, broad and slow spiking, and low levels of Ca 2+ -binding protein expression (Surmeier and Sulzer 2013). These physiological properties lead to increased cytosolic Ca 2+ and augment the metabolic burden in these neurons that is critical for selective neuronal degeneration (Surmeier and Sulzer 2013). Of note, the neurons in the VTA, which are LBD-resistant, have high neuronal activities as autonomous pacemakers, but express a high level of Ca 2+ -binding protein, indicating the importance of not only activity-dependent, but also signaling-path-specific Ca 2+ burden for the selective neuronal vulnerability in LBD (Surmeier and Sulzer 2013). Isradipine, a dihydropyridine calcium-channel (CaV1.3) blocker approved for the treatment of hypertension, is neuroprotective in animal models of PD (Chan et al. 2007;Guzman et al. 2010;Ilijic et al. 2011). This neuroprotective effect is mediated by inhibition of plasma membrane L-type calcium channels, which trigger mitochondrial oxidant stress and turnover (Guzman et al. 2010;Ilijic et al. 2011). These studies prompted a clinical trial evaluating the efficacy of isradipine to slow the clinical progression of PD in previously untreated early-stage PD patients. However, this trial indicated no significant effect (The Parkinson Study Group STEADY-PD III Investigators 2020). Attention has, therefore, been directed to other Ca 2+ channel-dependent mechanisms of activity-dependent Ca 2+ dyshomeostasis and signaling-path-specific selective fragility of neurons in LBD brains.
Lewy pathology is neuron-specific in LBD, suggesting a crucial role of intraneural α-synuclein in LBD pathology that is distinct from the cytoplasmic α-synuclein inclusions of glial cells in multiple system atrophy (Jucker and Walker 2013;Del Tredici and Braak 2020). Lewy pathology appears in neocortical pyramidal neurons, which do not have properties related to Ca 2+ dyshomeostasis, such as being autonomous pacemaker cells, exhibiting broad and slow spikes and low levels of Ca 2+ binding protein (Yamamoto et al. 2019). This pathology contributes to dementia in LBD, the second major cause of degenerative dementia (Braak et al. 2003;Chaudhuri et al. 2006). An unsolved question is, therefore, how intraneural α-synuclein oligomers pathologically can alter neuronal activity and intracellular Ca 2+ dynamics in neocortical neurons. By using intracellular injection of bioactive molecules or proteins such as inositol trisphosphate (IP 3 ), homer1a and amyloid-β through a patch pipette, how Ca 2+ and K + channels are involved in the regulation or pathophysiological change of neocortical pyramidal cell excitability and Ca 2+ dynamics are demonstrated Yamamoto et al. 2000Yamamoto et al. , 2002aYamamoto et al. , 2002bYamamoto et al. , 2005Yamamoto et al. , 2011. Interestingly, the results obtained using these methods correspond to those observed in neurons with physiologically produced IP 3 or homer1a proteins in the cytoplasm, or in neurons of 3xTg Alzheimer's disease model mice (Cui et al. 2007;Nakamura et al. 1999;Sakagami et al. 2005;Stutzmann et al. 2003;Yamamoto et al. 2000Yamamoto et al. , 2002aYamamoto et al. , 2002bYamamoto et al. , 2005Yamamoto et al. , 2011. The same methodology was used to introduce α-synuclein protein into pyramidal neurons in cortical slices from mice to investigate the effects and mechanisms of intracellular α-synuclein oligomers on neuronal excitability and Ca 2+ dynamics, as described below (Yamamoto et al. 2019).

Fig. 1 α-Synuclein oligomers and intraneural calcium dyshomeostasis
play key roles in the pathophysiological mechanism of LBD. Genetic and environmental risk factors promote LBD pathology, including the production of α-synuclein (αSn) oligomers and the disturbance of Ca 2+ homeostasis in LBD-vulnerable neurons, mutually strengthening the metabolic and proteostatic burden, and increasing the neuron-to-neuron propagation of αSn pathology and neuroinflammation. These pathophysiological alterations cause selective neuronal vulnerability and the spreading of LBD pathology. The metabolic and proteostatic burden includes mitochondrial dysfunction, the autophagy and lysosomal pathway and the ubiquitin proteasome system (UPS), and ER stress. LBD-vulnerable neurons share the features underlying Ca 2+ dyshomeostasis, such as being autonomous pacemaker neurons, having broad and slow spikes, and low levels of Ca 2+ binding protein. Note that neurons that do not have such Ca 2+ -related properties, such as neocortical neurons, are also prone to damage in LBD patients with cognitive decline

Aberrant activity-dependent calcium release from IP 3 receptors in central neurons caused by the association of α-synuclein oligomers with CABP1
To clarify pathophysiological changes in neuronal activity regulating intraneural Ca 2+ induced by α-synuclein oligomers, whole-cell recordings were obtained from pyramidal neurons located in slices of the mouse frontal cortex (Yamamoto et al. 2019). Immunoblotting analysis using anti-α-synuclein antibodies revealed that the recombinant α-synuclein incubated with dopamine at 37 °C for 3 days produced higher-order oligomers (αSNo) and fibrils, while the recombinant α-synuclein incubated without dopamine for 3 days was free of higher-order oligomers (αSN) (Yamamoto et al. 2019). After filtering to remove α-synuclein fibrils, αSNo and αSN solutions were used as pipette solutions, and the properties of action potentials in current clamp mode and the current charges during spike afterhyperpolarization (AHP) in voltage clamp mode were examined (Yamamoto et al. 2019). This examination revealed that intracellular application of αSNo significantly reduced spike frequency during current injection, elongated the duration of spike AHP, and enlarged AHP current charge compared with αSN (Yamamoto et al. 2019; Fig. 2). This αSNo-mediated Fig. 2 The electrophysiological detection and the mechanism of oligomeric α-synuclein-mediated aberrant Ca 2+ -induced Ca 2+ release (CICR). a Aberrant CICR was detected by a decrease in spike frequency (SK) and an enhancement of I AHP (afterhyperpolarization current) in αSNo (including higher-order α-synuclein oligomers)-applied neurons compared with αSN (free from higher-order α-synuclein oligomers)-applied neurons. After filtering to remove α-synuclein fibrils, αSNo and αSN solutions were used as pipette solutions for current clamp and voltage clamp recordings (Yamamoto et al. 2019). b The mechanism of oligomeric α-synuclein-mediated aberrant CICR was examined using drugs to modulate the channels and receptors that control intraneural Ca 2+ dynamics, and biomolecules or antibodies that regulate these channels and receptors (Yamamoto et al. 2019). The aberrant CICR is blocked by the extracellular application (non-italic text) of blockers of L-VDCC, SK, and IP 3 R, a Ca 2+ chelator, and an ER store depletor, and by the intracellular application (italic text) of calcium binding protein 1 (CaBP1), which is a neuron-specific regulator of IP 3 R gating and directly binds higher order α-synuclein oligomers (Yamamoto et al. 2019). The intracellular application of IP 3 and CaBP1 antibodies (Ab) both occlude the effect of αSNo. c A scheme illustrating the aberrant CICR during burst firing (from Yamamoto et al. 2019 with partial modification). (i) Endogenous CaBP1 (blue circle) binds IP 3 Rs and maintains Ca 2+ -dependent inactivation of IP 3 Rs (white rectangle). (ii) IP 3 elevation controlled by finely tuned neurotransmission or neuromodulation is required for physiological CICR from IP 3 Rs. GPCR/Gq: G-protein-coupled receptor/Gq protein. (iii) Intraneural α-synuclein oligomer (red ellipse) binds to endogenous CaBP1 and allows aberrant CICR from IP 3 Rs (red rectangle) independent of IP 3 turnover, which enhances Ca 2+ dysregulation. (iv) CaBP1 Ab binds endogenous CaBP1, prevents CaBP1 regulation of IP 3 Rs and triggers aberrant CICR in a similar manner to the α-synuclein oligomer.
(v) CaBP1 binds α-synuclein oligomer and blocks oligomeric α-synuclein-mediated aberrant CICR alteration was triggered by spike-induced Ca 2+ release from IP 3 Rs functionally coupled with L-VDCC and small conductance Ca 2+ activated K + (SK) channels under the application of blockers for the channels or receptors responsible for intraneural Ca 2+ dynamics (Yamamoto et al. 2019; Fig. 2). This Ca 2+ -dependent functional triad consisting of L-VDCCs, IP 3 Rs and SK channels is well established and is linked to spike-triggered Ca 2+ inflow and Ca 2+ release (Ca 2+ -induced Ca 2+ release; CICR) from IP 3 Rs in neurons of the neocortex and amygdala, and contributes to the regulation of neuronal excitability and synaptic plasticity Yamamoto et al. 2000, 2002a, b, Faber et al. 2010, Power and Sah 2005Yamada et al. 2004;Fig. 2c, iii). In contrast with previous reports that emphasized how the physiological upregulation of IP 3 turnover is finely tuned by synaptic stimulation or neuromodulation and is necessary for spikeinduced or IP 3 -induced Ca 2+ release from IP 3 Rs in central neurons (Cui et al. 2007;Faber et al. 2010, Nakamura et al. 1999Sah 2005, 2008;Stutzmann et al. 2003;Yamada et al. 2004;Yamamoto et al. 2000Yamamoto et al. , 2002aYamamoto et al. , 2002bFig. 2c, ii), the oligomeric α-synuclein-mediated CICR from IP 3 Rs presented here was independent of increased IP 3 production, because the phospholipase C (PLC) blocker, U73122, failed to inhibit it (Yamamoto et al. 2019; Fig. 2b). Such an unusual mode of CICR provoked by highly frequent neuronal activity, independent of IP 3 turnover, does not usually occur in central neurons because the regulation of IP 3 R gating exhibits bell-shaped dependence on somatic Ca 2+ concentration (Bezprozvanny et al. 1991). This mode of CICR can therefore be regarded as pathological, forcing an excess Ca 2+ burden on neurons, surpassing a negative feedback regulation of spike firing (Fig. 2c, iii). Accordingly, via this channel coupling, α-synuclein oligomers provoke the aberrant CICR from IP 3 Rs, which is triggered by Ca 2+ influx via L-VDCCs during repetitive firing, followed by elongation of SK channel opening (the prolongation of I AHP ) and decreased spike frequency (Yamamoto et al. 2019). Consequently, in neocortical pyramidal neurons, the occurrence of this aberrant mode of CICR can be detected by examining the elevation of I AHP charge and the reduction in spike frequency (Fig. 2c i, iii; Yamamoto et al. 2019).
IP 3 R has two separate binding sites for Ca 2+ and IP 3 , which are allosterically regulated by the two ligands. The binding of one ligand facilitates additional binding of the other (Berridge 1998;Verkhratsky 2005); therefore, IP 3 R responds to the increase in neuronal cytosolic Ca 2+ and IP 3 , opens, and releases Ca 2+ from the ER in an activity-dependent manner (Yamamoto et al. 2000(Yamamoto et al. , 2002aYamada et al. 2004, Nakamura et al. 1999, Larkum et al. 2003. The PLC blocker, U73122, failed to block Ca 2+ release but intracellular application of IP 3 occluded the effect of αSNo; therefore, α-synuclein oligomers modulate IP 3 R gating and mediate the aberrant form of CICR from IP 3 Rs during repetitive spikes, without enhancing Ca 2+ influx or IP 3 production in neocortical neurons (Yamamoto et al. 2019;Fig. 2c, iii).
The gating of IP 3 R is not only regulated by IP 3 or Ca 2+ binding, but also by various proteins that interact with IP 3 R (Choe and Ehrlich 2006;Foskett et al. 2007); therefore, αSNo could be linked to a protein that directly binds IP 3 R and regulates IP 3 R gating in central neurons. Among the binding partners of IP 3 R, Ca 2+ -binding protein 1 (CaBP1) is the most promising candidate, because CaBP1 is (1) a Ca 2+ -binding protein expressed in the cytosol of rodent and human central neurons (Laube et al. 2002;Bernstein et al. 2003;Kim et al. 2014), (2) a protein that preferentially interacts with oligomeric α-synuclein (Betzer et al. 2015), and (3) a binding partner and negative regulator of IP 3 Rs under high intraneural Ca 2+ concentration by means of Ca 2+ -dependent inactivation (Haynes et al. 2004;Kasri et al. 2004;Li et al. 2013). CaBP1 is a neuronal Ca 2+ -binding protein splice variant, a sub-branch of the calmodulin superfamily, which includes Ca 2+ -sensor proteins that regulate various Ca 2+ channel targets (Yang et al. 2002;Haeseleer et al. 2000). CaPB1 has four EF-hand Ca 2+ -binding motifs, and can bind and regulate IP 3 R under high intraneural Ca 2+ concentration (Haynes et al. 2004;Kasri et al. 2004;Li et al. 2013). Once αSNo binds to CaBP1 and pulls it away from IP 3 R, thus disrupting Ca 2+ -dependent regulation of IP3R, an aberrant CICR from IP 3 R can occur without enhancing Ca 2+ influx or cytosolic IP 3 concentration.
The effects of intracellular application of a CaBP1 antibody (Ab) and CaBP1 on αSNo-mediated change were compatible with this hypothesis. CaBP1 Ab occluded the effect of αSNo, which was blocked by nifedipine and heparin, indicating that αSNo-mediated capture of CaBP1 is necessary and sufficient for the aberrant CICR from IP 3 R (Yamamoto et al. 2019;Fig. 2c, iv, v). By contrast, calmodulin, which is another binding partner and regulator of IP 3 R (Yang et al. 2002;Taylor and Tovey 2010) and directly binds α-synuclein (Lee et al. 2002;Martinez et al. 2003), and a calmodulin antibody, failed to counteract αSNo-mediated action (Yamamoto et al. 2019 ; Fig. 2b). These electrophysiological observations were further supported by immunoprecipitation experiments that demonstrated the direct binding of higher-order α-synuclein oligomers larger than 100 kDa with CaBP1 (Yamamoto et al. 2019). Together, these electrophysiological findings demonstrate that the target of α-synuclein oligomers was CaBP1, and confirmed the direct association of α-synuclein oligomers greater than 100 kDa with CaBP1, resulting in aberrant CICR from IP 3 R (Yamamoto et al. 2019). These results are consistent with previous studies showing that transgenic α-synuclein mice exhibit augmented long-lasting Ca 2+ transients in response to repetitive stimulation in vivo (Reznichenko et al. 2012), and that neocortical pyramidal cell excitability is reduced by injecting α-synuclein oligomers (Kaufmann et al. 2016), but emphasize that α-synuclein oligomers cause this activity-dependent signaling-path-specific CICR surpassing the regulation of spike firing.
IP 3 and CaBP1 have opposing effects on the IP 3 R channel under high intracellular Ca 2+ concentrations (Haynes et al. 2004;Karsi et al. 2004;Li et al. 2013). IP 3 obstructs the inter-subunit interaction of IP 3 R and encourages IP 3 R channel opening (Choe and Ehrlich 2006;Li et al. 2013). By contrast, CaBP1 binds IP 3 R and prevents the inter-subunit interaction of IP 3 R when the somatic concentration of IP 3 is low, thereby hindering IP 3 R channel opening in a Ca 2+ -dependent manner Choe and Ehrlich 2006;Li et al. 2013; Fig. 2c i). These mechanisms clarify why IP 3 and CaBP1 Ab occlude and heparin and CaBP1 inhibit the action of αSNo (Fig. 2c, ii, iv, v); oligomeric α-synuclein-mediated removal of CaBP1-mediated regulation of IP 3 R, but not the Ca 2+ buffering effect of CaBP1, is essential for aberrant CICR from IP 3 R (Fig. 2c, iii).

A potential mechanism of oligomeric α-synuclein-mediated calcium dysregulation in early pathology of LBD-vulnerable neurons
IP 3 R is localized on ER membrane connected with mitochondria, known as the mitochondria-associated ER membrane, and increased Ca 2+ transfer from the ER via IP 3 Rs to mitochondria inhibits autophagy (Szabadkai et al., 2008;Decuypere et al. 2011). Chronic aberrant CICR from the IP 3 R in the presence of intraneural α-synuclein oligomers may increase the risk of activity-dependent mitochondrial stress through the IP 3 R-mitochondrial connection, and may lead to neuronal fragility in oligomeric α-synuclein-bearing neurons. This notion is supported by previous studies indicating that α-synuclein can alter mitochondrial Ca 2+ homeostasis by enhancing ER-mitochondria interactions (Cali et al. 2012), and that α-synuclein can be localized to the mitochondria-associated ER membrane (Guardia-Laguarta et al. 2014).
The ER is a continuous "neuron-within-neuron" network that extends to all parts of the neuron, including the spines, cell soma, and synaptic endings, and that supports regional and long-distance Ca 2+ homeostasis (Berridge 1998;Öztürk et al. 2020). Ca 2+ signals can transmit through the cytosol by CICR from the ER, and induce regional or global communication within the cell, at a pace that is slower than action potential propagation in the plasma membrane. CICR can be mediated by IP 3 Rs or ryanodine receptors and can be augmented by elevated cytosolic Ca 2+ (Berridge 1998;Öztürk et al. 2020). The CICR from IP 3 Rs propagates as a Ca 2+ wave along the ER via IP 3 Rs and ryanodine receptors throughout the somatodendritic portion and the nucleus (Power and Sah 2002;Watanabe et al. 2006;Ross 2012). This normal Ca 2+ wave propagating from dendrite to soma and nucleus, is initiated only when strong synaptic stimulation or synaptic stimulation concurrent with repetitive spikes occurs (Power and Sah 2002;Watanabe et al. 2006;Ross 2012). This is mainly dependent on IP 3 R which is distributed in the soma and dendrites, thereby regulating neuronal excitability and synaptic plasticity (Power and Sah 2002;Watanabe et al. 2006;Ross 2012). In contrast, it is noteworthy that repetitive spikes alone, independent of synaptic input, are enough to cause the aberrant CICR from the ER via IP 3 Rs in the presence of α-synuclein oligomers (Yamamoto et al. 2019;Fig. 2c, iii). Subsequent to backpropagating action potentials from the soma to dendrites (Waters et al. 2005), this aberrant CICR can cause the chronic aberrant Ca 2+ wave to be propagated along the soma-dendritic region (Yamamoto et al. 2019; Fig. 3). A sporadic PD risk gene, BST1, encodes cyclic ADP-ribose hydrolase 2, which synthesizes cyclic ADP-ribose, a ryanodine receptor agonist (Satake et al. 2009;Saad et al. 2011). BST1 variants can disturb normal channel function of the ryanodine receptor, another Ca 2+ release channel in the ER, and can enhance the aberrant CICR via IP 3 Rs to promote propagation of dysregulated Ca 2+ waves (Yamamoto et al. 2019;Fig. 3). Chronic occurrence of this aberrant CICR and Ca 2+ wave may increase the risk of distinct activity-dependent Ca 2+ dyshomeostasis and may lead to pathological intraneural spreading and neuronal fragility specific to repeatedly activated signaling path in oligomeric α-synuclein-bearing neurons, although this remains to be studied. Considering that oligomeric α-synuclein accumulates first at presynaptic terminals in LBD (Bridi et al. 2018), and that the pathological change of LBD-vulnerable neurons is a dying back-phenomenon, which initiates at synaptic terminals and progresses along the axon, affecting homeostasis and survival of neuronal cell bodies (Cheng et al. 2010;Bridi et al. 2018), a tentative mechanism of oligomeric α-synuclein-mediated aberrant calcium dyshomeostasis promoting early neuronal pathophysiological change in LBD-vulnerable neurons, is proposed in Fig. 3.
Immunohistochemical studies reveal that among central neurons, the expression level of CaBP1 is lowest in SNc neurons, which are the most fragile in PD (Laube et al. 2002;Kim et al. 2014). The scarcity of CaBP1 in SNc neurons suggests that the smallest amount of α-synuclein oligomers can induce the aberrant CICR described here, and that this may account for by far the highest vulnerability of SNc neurons. The L-VDCC blocker, isradipine, suppresses Ca 2+ influx via CaV1.3 L-VDCC and inhibits degeneration of SNc neurons (Chan et al. 2007), although this drug failed to slow the progression of PD (The Parkinson Study Group STEADY-PD III Investigators 2020). Given that L-VDCC blockers suppress aberrant CICR from IP 3 Rs (Yamamoto et al. 2019), and lower the risk of PD (Ritz et al. 2010;Ascherio and Schwarzschild 2016), they may reduce the risk of aberrant CICR propagation along the ER in the somatodendritic area, and may have potential in protecting LBD-vulnerable neurons from damage and the spread of Lewy body pathology. Fig. 3 A potential mechanism of oligomeric α-synuclein-mediated calcium dyshomeostasis promoting early pathology in LBD-vulnerable neurons. a In LBD-vulnerable neurons, various LBD risk factors trigger a dying-back pathology that is initiated at synaptic terminals and progresses along the axon with oligomeric α-synuclein (αSn) appearing in cell bodies. During burst firing, the oligomeric αSn-mediated CICR from IP 3 Rs propagates as an aberrant Ca 2+ wave via IP 3 Rs and ryanodine receptors along the somatodendritic portion of the ER (Ca 2+ : black dot). b A proposed retrograde bottom-up model of αSn propagation reinforced by the aberrant Ca 2+ wave in LBD-vulnerable neurons. Retrograde propagation of αSn pathology (upper left) brings somatodendritic αSn oligomers, which cause chronic aberrant CICR propagation (aberrant Ca 2+ wave) during burst firing (upper right). This Ca 2+ dysregulation in turn promotes the Ca 2+ burden, the secretion of αSn from dendrites (lower right), and transmission of αSn pathology to nearby synaptic terminals (lower left). Together with neuronal degeneration of LBD-vulnerable neurons, the retrograde propagation of αSn pathology in presynaptic LBD-vulnerable neurons is initiated (lower left, upper right). This mechanism specific to repeatedly activated signaling path can account for the propagation of LBD pathology