Molecular Neurobiology

, Volume 49, Issue 3, pp 1270–1281

Autophagy Coupling Interplay: Can Improve Cellular Repair and Aging?

Authors

  • Deepak Chhangani
    • Cellular and Molecular Neurobiology Unit, Indian Institute of Technology
  • Sachin Chinchwadkar
    • Cellular and Molecular Neurobiology Unit, Indian Institute of Technology
    • Cellular and Molecular Neurobiology Unit, Indian Institute of Technology
Article

DOI: 10.1007/s12035-013-8599-z

Cite this article as:
Chhangani, D., Chinchwadkar, S. & Mishra, A. Mol Neurobiol (2014) 49: 1270. doi:10.1007/s12035-013-8599-z

Abstract

Regular protein synthesis is a needful and complex task for a healthy cell. Improper folding leads to the deposition of misfolded proteins in cells. Autophagy and ubiquitin–proteasome system (UPS) are the conserved intracellular degradation processes of eukaryotic cells. How exactly these two pathways cross talk to each other is unclear. We do not know how the impairment of autophagy or UPS leads to the disturbance in cellular homeostasis and contribute into cellular aging and neurodegeneration. Here in this review, we will focus on the functional interconnections of autophagy and UPS, and why their loss of function results in abnormal aggregation of misfolded proteotoxic species in cells. Finally, we enumerate and discuss the crucial inducers of autophagy pathways and elaborate their intersection steps, which have been considered to be advantageous in aging linked with the abnormal protein aggregation. The final goal of this review is to improve our current understanding about multifaceted properties and interactions of autophagy and UPS, which may provide new insights to identify novel therapeutic strategies for aging and neurodegenerative diseases.

Keywords

AutophagyUbiquitin proteasome systemAgingMisfolded proteinsCell death

Introduction

Accumulation of aberrant proteins imposes a major risk to health of cells and represents a serious defect in the selective misfolded elimination process. Protein translation allows the synthesis of nascent polypeptide chains which can swiftly fill the urgent requirement of cellular environment. But what factors determine the specific selective recognition of damaged or poor proteins and distinguish them from normal proteins is still not known. Despite the apparent abundance of protein quality control system (QC), governed by ubiquitin–proteasome system (UPS) and autophagy pathways, which are two chief proteolytic mechanisms [1, 2], still the intracellular aggregation of misfolded proteinaceous species create a threat full unavoidable challenge. Therefore, it is crucial for us to understand how UPS and autophagy are linked and coordinate to each other in the clearance of nonnative proteins.

Ample numbers of recent studies indicate that cells trigger numerous accurate efforts even at ribosomal level to maintain the protein quality control mechanism in cells [3, 4]. But under insufficient folding, translational errors and mutations cause aggregation of misfolded proteins in cells which subsequently sequester various molecular chaperones, transcriptional factors, E3 ubiquitin ligases, p62, Atg (autophagy-related) proteins, and microtubules in cells [59]. Cells employ dynamic and reliable strategies to sense translations errors and improve the cotranslational folding of nascent polypeptide chains at ribosomal site [10, 11]. But failure or insufficient chaperone capacity lead to the massive accumulation of abnormal ubiquitin-enriched inclusion bodies displaying a high possibility of impaired UPS and/or dysfunction of basal autophagy.

Perhaps, recent findings by several groups have observed that most probably autophagy and UPS do cross talk to each other or perform collaborative function of eliminating misfolded proteins in cells [12, 13]. Currently, it is not clear how attenuation of abnormal protein degradation initiates loss of connections between these processes. How misfolded protein generation mediates manipulation of activation levels of the UPS and autophagy, and how they divide the overload of wasteful-aggregation, has not been elucidated. In several studies, it has been suggested that detailed understanding of disposal of abnormal proteins may provide the new insights for the effective treatment of numerous protein conformational disorders [14]. But still it is very important and a challenge for us to understand “how aggregation of misfolded protein lead to pathological characteristic in cells.”

Mounting evidence suggests that impairment of UPS and dysfunction of autophagy leads to aging and generates pathological conditions; this might represent a common mechanistic link between various neurodegenerative diseases and aging. This review presents the recently open concepts and findings that specifically describe the cumulative functions of UPS and autophagy against protein aggregation. How these proteolytic mechanisms regulate the disaggregation and promote the removal of misfolded proteins? This may be crucial to identify novel targets or inducers for pharmacotherapy of proteotoxic deposition diseases and aging. A detailed and systematic understanding of the molecular interdependency of these two proteolytic (UPS and autophagy) pathways may provide a better opportunity for an early diagnosis and therapeutic treatments for numerous aging-associated diseases.

Constructive Cross Talk Among Autophagy and UPS is Simply a Dependency-Compromise or a Crucial Mechanism for Survival?

Discovering the biological cellular catabolism has been implicated in several protein conformational disorders such as aging and neurodegeneration. Short lived, aggregated, nonnative, or damaged proteins are targeted for their destruction or removal by the mutual efforts of UPS and autophagy [1517]. Dysfunction of these cellular catabolism pathways leads to severe defects in intracellular mechanisms and subsequently provokes the failure of cellular homeostasis. However, such a loss-of-function study is rarely addressed in detail. Careful orchestrated observations and improved understanding of cross talk among these two cornerstones (UPS and autophagy) will provide novel therapeutic insights into the cellular management of misfolded protein clearance.

In this section of review, we represent a comprehensive mechanism of protein misfolding and aggregation or inclusion bodies deposition into different cellular compartments (Fig. 1). To date, several studies [18, 19] have summarized that modulated activities of UPS and autophagy may play a pivotal role in various neurodegenerative diseases linked with the elimination of accumulated misfolded proteins. Still, our knowledge is limited to understand how these two proteolytic pathways are linked to each other and provide an integrated cytoprotection against multifactorial proteotoxic effects. In this section, we discuss how the loss-of-function or defects in these pathways generate serious malfunction in cells and finally lead to proteostasis imbalance.
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Fig. 1

Schematic representation of the molecular events leading to misfolded proteins aggregation in cells. Why do some proteins adopt aberrant forms and become prone towards aggregation in cells? Insufficient chaperone capacity and poor degradation efficiency lead to the deposition of multifactorial toxic proteins in cells. Functional autophagy and ubiquitin–proteasome system (UPS) promote the selective elimination of early toxic polypeptides from the cells. Dysfunction or failure of autophagy or UPS raises a huge possibility of asymmetric distribution of damaged proteins and initiates the progression of potentially toxic protein aggregation and aging associated diseases

UPS and Autophagy: Mutual Tight Regulation and Delicate-Integrated-Sharing is Compulsory

Nuclear, cytoplasmic, and extracellular inclusions are formed by the aggregation of misfolded protein species and their ubiquitin positive characteristic feature represents a chief hallmark of several neurodegenerative diseases [20]. Autophagy or self-eating is a cellular mechanism to degrade damaged or poor cellular constituents including large protein aggregates [21]. Ubiquitin proteasome system promotes the selective degradation of short-lived intracellular proteins and plays an important homeostatic role in cells [22, 23]. However, the mutual role of autophagy and UPS in the elimination of abnormal protein aggregates remains unexplained. Where both the crucial cellular processes cross talk to each other and how their cumulative dysregulation contributes in the pathogenesis of various neurodegenerative diseases is not known. In principle, alternations and sequestration of several factors associated with these pathways can perturb the numerous cellular renovation functions and potentially influence the deprivation or imbalance in the degradation of proteotoxic species.

Does deregulation or impaired function of autophagy and UPS play a crucial role in cell death induced by misfolded proteins? Recently, it has been shown that aberrant function of autophagy and UPS causes protein accumulation, leading to neuronal impairment or pathology of neurodegeneration [24, 25]. Inhibition of proteasome function generates oxidative stress and aggregation of nonnative proteins; induction of a specific kind of autophagy, i.e., chaperone-mediated autophagy (CMA), provides a compensatory support during oxidative stress conditions [26]. In a similar process-based manner, it was observed that autophagy is stimulated by proteasome inhibitor-induced ER stress through IRE1-mediated pathway and both cellular degradation systems are functionally linked to alleviate ER stress [27]. Unfolded proteins can be recognized by ER lumen-mediated unfolded protein response (UPR), and under UPR-induced conditions is generation of autophagosome-like structures that counterbalance endoplasmic reticulum expansion [28].

This is likely an important question: “How misfolded protein aggregation stimulates or exerts the steady-state level of cellular degradation mechanism?” Of course, deregulated degradation of existing old or damaged proteins without the replacement with new nascent polypeptides chains would be harmful for cells. Therefore, it is necessary to execute the regulative, compensatory-linked selective and bulk degradation of damaged proteins distinctly by autophagy and UPS in cells. How these two proteolytic pathways are synergistically linked to each other and alleviate proteotoxicity in cells is not well known. One determinant is probably the ubiquitin-mediated selective delivery of the misfolded proteins into the proteasome protein complex which enriched with proteases and provides cytoprotection against damaged proteins [1]. The improper folding of proteins leads to their quick destruction; near about 30 % of newly synthesized polypeptide chains rapidly eliminate from the cells [29]. UPS is responsible for the intracellular protein degradation pathway and the selectivity of protein degradation is governed by E3 ubiquitin ligases of the UPS pathway [30]. Autophagy is a major catabolic mechanism for the clearance of old or poor cytoplasmic components including organelles, and therefore provides cytoprotective response against several stress conditions [31, 32]. Emerging studies suggest that autophagy is also involved in selective removal of protein aggregates from the crowded cellular milieu known as “aggrephagy” [33].

Each cell has a limited capacity to degrade abnormally folded proteins via UPS pathway; overproduction of misfolded proteins make them accumulate in cells and they form big inclusion-like structures known as aggresomes [34]. Continuous aggregation of misfolded proteins induces intracellular deposition of ubiquitin-rich aggresomes or inclusion bodies-like structures [35]. This abnormal repetitive accumulation of misfolded proteins finally overwhelms the degradation efficiency of proteasome and impairs the entire UPS pathway [3638]. To avoid such noxious protein aggregation-mediated condition which may cause cell death due to proteasomal impairment, cells immediately choose another route for the clearance of toxic-misfolded proteins. Recently, it has been shown that inactivation of proteasome function induces basal autophagy flux, probably with the help of hypoxia-inducible transcription factor 1 (HIF-1α)/sima and Atg genes [39]. Under failure of UPS, probably rapid autophagy induction is another survival pathway that partially compensates for the lack of proteasomal function and tries to selectively eliminate the aggregates of misfolded proteins from the dense cellular pool filled with damaged proteins [40].

Malfunction of Intracellular Protein Degradation: First Consequence is Compromise Then Massive Concomitant Aggregation and Finally Cell Death

What types of overall molecular mechanisms exist by which the ordered elimination of accumulated and aggregated proteins take place in a normal cell is still unknown. The exponential increase of misfolded protein aggregation may impair the functional states of UPS and autophagy, and causes most adult-onset human neurodegenerative disorders [4144]. How the ubiquitination of critical proteins regulates autophagy pathways is not well explored. Here, we discuss an important role of various E3 ubiquitin ligases which are required to determine the emerging relationships between autophagy and UPS (Fig. 2). Despite the continuous accumulation of misfolded proteins in insoluble aggregates, the intricate molecular mechanisms governed by E3 ubiquitin ligases potentially facilitate the clearance of abnormally folded proteins via ubiquitin–proteasome and autophagy–lysosome pathways [45, 46]. Here in this section, we review and summarize available evidence for the role of various E3 ubiquitin ligases implicated in the removal of harmful protein aggregates mediated by a cross talk between two key intracellular proteolytic systems: the UPS and the autophagy.
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Fig. 2

Autophagy and ubiquitin–proteasome system are cytoprotective pathways; their induction alleviates cellular stress and proteotoxicity mediated by the aggregation of misfolded proteins. Excessive generation of abnormal proteins leads to the impairment of proteasome system and probably autophagy, another major route for the degradation of intracytosolic proteotoxic aggregates. Stimulating the autophagy mediated clearance of aberrant protein aggregates can improve the overall functionality of cell. Another strategy is to identify new drugs that can improve the cross talk or cumulative function of autophagy and UPS to deal with these aggregated mutant proteins. Can upregulating autophagy and UPS activities promote the longevity? Understanding the molecular mechanisms behind this question may give the solution for anti-aging effects

Recent experimental studies and literature have provided growing evidences for the involvement of E3 ubiquitin ligases in the clearance of misfolded proteins via different approaches in cells [47]. However, the mechanisms by which E3 ubiquitin ligases regulate the integration of abnormal proteins’ removal by collaboration between proteasome and autophagy remain to be elucidated. The central question is that “how do E3 ubiquitin ligases engage both proteasome and autophagy process in the degradation of misfolded proteins and simultaneously provide specificity in terms of recognition?” It has been shown that in familial Parkinson’s disease, a really interesting new gene (RING) homologous to E6-AP carboxyl terminus (HECT) hybrid E3 ubiquitin ligase PARKIN (PARK-2) and its regulatory kinase PINK1 (also known as PARK6) are generally mutated and induce mitophagy [4850]. Selective recruitment of parkin induces elimination of defective or nonfunctional mitochondria by autophagosomes. This study suggests that loss of function of parkin plays a significant role in the pathogenesis of Parkinson’s disease due to aberrant removal of poor or old mitochondria [51].

It is hard to predict the half-life of a misfolded protein because most probably, due to the free availability of proteolytic machinery, cells often prefer their immediate removal from the various cellular compartments. How parkin participates and shares own identity among autophagic and UPS-mediated degradation of misfolded proteins is not clear. Recently, it has been shown that parkin potentially influences the ubiquitylation scheme of the mitochondrial proteome and most likely control mitochondrial homeostasis [52]. There are few additional evidences that suggest parkin-mediated Lys(63)-linked polyubiquitination induces sequestration of misfolded proteins by aggresome–autophagy pathway and consequently removes them by autophagy [5355].

Degradation of poor or old bulk cytoplasm for recycling is achieved by autophagy. Although most of the studies explored the mechanism of damaged mitochondrial degradation by autophagy, but the exact molecular mechanism by which selective degradation or clearance of mitochondria via ubiquitination is not well known [5660]. Recently, it has been shown that an E3 ubiquitin ligase RING finger protein 185 (RNF185) localizes on mitochondrial outer membrane, and interaction of RNF185 with BCL2/Adenovirus E1B 19 kDa Protein-Interacting Protein 1 regulates selective autophagy [61]. Defective mitochondria generate reactive oxygen species, therefore, finally lead to oxidative damage and cell death. Elimination of misfolded proteins is a critical process specifically that plays a significant role in the maintenance of redox homeostasis in cells. Superoxide dismutase (SOD1) mutations have suggested that mutant SOD1 proteins stimulate neuronal toxicity and neuronal death [62].

Interaction of SOD1 aggresomes with E6-AP, a putative HECT domain E3 ubiquitin ligase, induces their degradation and provides cytoprotection against proteotoxicity mediated by mutants SOD1 proteins [63]. E6-AP also promotes the elimination of misfolded expanded polyglutamine proteins and interaction with Hsp70 chaperone enhances its quality control function in cells [6, 64]. Endoplasmic reticulum-associated E3 ubiquitin ligase glycoprotein 78 (gp78) promotes degradation of various critical substrates such as cystic fibrosis transmembrane conductance regulator, ataxin-3, SOD1, and KAI1 [6567]. Recently, it has been shown that gp78 regulates mitophagy by Mfn1 mitochondrial fusion factor [68].

Autophagy or Self-Eating: Is It a Constructive Friend or Destructive Foe Against Aging Induced by Stress?

Accumulating evidences suggest that autophagy is an essential process for the removal of altered or abnormal proteins and significantly regulates cellular homeostasis [42]. Dysfunction of autophagy generates numerous diseases such as cancer and neurodegeneration, suggesting that a regular activation of autophagy is necessary for extended longevity [69]. In this section, we will discuss the existing knowledge on the contribution of autophagy to maintain the cellular aging. Despite we know the fact that autophagy fights against diseases through cellular self-digestion mechanism but how autophagic failure is associated with loss of cellular quality control process and aging remains unclear. Under stress conditions, the activation of autophagy is a crucial and cytoprotective in nature instead of cellular self-eating process [70, 71]. Recently, it has been studied that under genotoxic stress conditions, inhibition of autophagy promotes apoptosis by regulating p62-dependent p38 activation [72]. But how this deregulation in autophagy induces molecular pathomechanism of aging is not known.

Autophagy principally encompasses aberrant proteins or poor organelle degradation by various routes. The cellular survival responses triggered by autophagy against stress conditions include macroautophagy, microautophagy, and CMA. Overall autophagy has a prominent role in determining the life span and aging of an organism [73]. Damaged cytoplasmic materials including proteins that are linked with neurodegeneration disorders such as expanded polyglutamine mutant huntingtin, tau, α-synuclein, and mutant SOD1 proteins are cleared by autophagy [24, 7477]. Which processes provide autophagy-mediated cytoprotection? Cellular survival under stress conditions by the support of autophagy and lead to healthy aging are unexplored. Inhibition of autophagy generates neurodegeneration like pathological hallmarks in mice and activation of autophagy suppresses the proteinopathies and enhances the survival of neurons [78, 79]. These studies suggest that autophagic-degradation efficiency declines during aging and induces the production of multifactorial intracellular proteotoxic devastated products. In a long life span of an organism, improper removal and further accumulation of such unwanted cytotoxic material lead to aging and neurodegeneration like pathological symptoms [80].

Exposure to a variety of stressors induces accumulation of toxic protein products and raises multimeric disturbances which eventually induce cell death. However, the molecular mechanisms that link toxic protein aggregation, cell death, deregulated quality control system, and aging have not been well demonstrated. Accumulating evidences suggest that impaired or inefficient autophagic proteolytic functions promote the intracellular misfolded protein aggregation and aging [8183]. Overall, these studies give the first fragmentary indication that induces autophagy which can contribute in the longevity and healthy aging. In Caenorhabditis elegans, mutations in Atg genes cause autophagy inhibition and reduce the longevity [84]. Aged pancreatic islets from rats represent reduced Atg8 and Atg7 protein levels that indicate declined or impaired basal autophagic activity [85]. Aging is a genetic process; recently it was observed that gene therapy treatment and increased expression of few genes such as Sirtuin 1 (SIRT1) may reduce aging and improve the life span of an organism [8688]. Interestingly, exposure to various stressors including starvation regulates autophagy even under neonatal stage [8991].

Removal of old or damaged organelles and recycling of cellular waste are normal catabolism and anabolism processes in a healthy cell. Autophagy and UPS are dynamic cellular catabolic pathways; these mechanisms are regulated by several kinases, transcription factors, and phosphatases [92, 93]. Caloric restriction has been observed to have a potential physiological inducer role in autophagy. Interestingly, recently it has been shown that caloric restriction induces the autophagy and increase life span extension in mice, nematodes, flies, and even plants [73, 90, 9496]. Still, the precise molecular mechanisms by which dietary restriction-mediated autophagy extend life span of an organism are not very clear. It is possible that various genes regulate autophagy and influence the life span of an organism; several genes were identified which increase the life span of yeast [97, 98]. Similarly, in C. elegans, dietary restriction factor and various age-related genes contribute in the life span extension and aging process [73, 99101].

Taken together all these observations, we can postulate that in an entire life span, autophagy-mediated clearance of cellular waste contributes in aging reduction mechanism. But dysregulation of such a dynamic process may cause imbalance in cellular fitness. Under such conditions, elevated cellular stresses may influence a negative impact on ubiquitin proteasome pathway. Earlier, it has been shown that proteasome activity declines in the spinal cord of aging rats and may be one of the causative factors of neuronal death [102]. Many studies summarize the crucial role of ubiquitin proteasome pathway in aging [103105]. These observations clearly point out that direct cross talk of autophagy and UPS can facilitate the destruction of intracellular waste and regular removal of such damaged materials can boost the level of cellular health. Therefore, the search and detailed understanding of molecular mechanisms, which can specifically induce the activity of UPS and autophagy or both the pathways, may contribute in the regulation of neuropathological events related with the aging of the central nervous system (CNS). In the next section of this review, we will focus on various known molecular strategies wherein alterations can slow down the specific cellular aging events specifically influenced by the functions of UPS and/or autophagy.

Enhancers for the Clearance of Misfolded Proteins: Effective Strategies to Prevent or Slow Down the Formation of Inclusions in Diseases

Can the accelerating removal of toxic proteins via functional potentiation of autophagy and UPS with pharmacological therapeutic strategy provide relaxation against proteotoxic diseases? Does accumulation of misfolded proteins inhibit the overall catabolic mechanism of cells and causes age-related degenerative diseases? These questions are challengeable as well as important to understand the pivotal mechanism of longevity and healthy aging. A wide range of literature represents that decline in the catabolic activity of autophagy and UPS perturbs the functions of critical regulators of these pathways and therefore leads to the accumulation of toxic protein aggregates [106108]. Here, in this section, we will elaborate that how various inducers of autophagy and UPS pathways can promote the elimination of wasteful proteins and generate anti-aging events in cells (Fig. 3).
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Fig. 3

Proposed effective molecular mechanisms to enhance the degradation of cytotoxic protein aggregates. Right now, there are no clear and potential cellular mechanisms known to efficiently remove the deposition of intracytoplasmic aggregate-prone proteins. Numerous studies have provided robust support for our better perception to realize that identifying new generic and chemical strategies which can modulate the function of proteolytic mechanisms (autophagy and UPS) at various steps may enhance the removal of toxic, aggregation-prone proteins. Identifying new pharmacological modulators for linking misfolded protein recognition strategies with proteolytic mechanisms can improve the longevity affected by the altered proteins

There is a tight and complex relationship that persists between autophagy and UPS to specifically identify the aggregation of misfolded proteins and stimulate their degradation [109]. In dendritic cells, an intracellular receptor “nucleotide-binding oligomerization domain-containing-2” (NOD2) serves as bacterial sensor, NOD2 is essential for muramyldipeptide-mediated autophagy induction in primary human antigen-presenting cells and monocyte-derived dendritic cells [110]. Recently, it has been shown that beclin 1-derived Tat-beclin-1 binds with Golgi-Associated Plant Pathogenesis-Related protein 1, a newly identified autophagy regulator, and induces a cellular autophagy response [111]. This autophagy-inducing peptide has a therapeutic potential to slow down the human diseases associated with aggregates formation. Interestingly, in cancer cells, an epidermal growth factor receptor antibody “cetuximab” has been shown to induce autophagosome formation by reducing the levels of B cell lymphoma 2 and hypoxia inducible factor-1 alpha [112]. A human single-chain fragment variable, HW1 associates with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) enhances autophagy-mediated cell death in both TRAIL resistant as well as TRAIL-sensitive cancer cells [113].

In aggresomes, a microtubule-associated deacetylase, Histone deacetylase 6 (HDAC6), associates with polyubiquitinated misfolded proteins and facilitates the recruitment of aberrant proteins into aggresomes [114]. In Drosophila melanogaster, a recent study suggests that autophagy provides a compensatory support mediated by HDAC6 under impairment of UPS function [115]. Dysfunction in any out of these two proteolytic pathways imbalances the wasteful-clearance load of cells and makes them prone to generate additive obsolete cellular proteins. Identification of molecules that can enhance the decline in activities of these proteolytic systems may overcome their scarcity and initiates rescue events against proteotoxic conditions. Screening of small molecules or related gene products as inducers for autophagy or UPS pathways is also a potential strategy for the elimination of mutant-aberrant proteins. Recently in a high-throughput cell-based functional screening, transmembrane 9 superfamily member 1 was identified as autophagosome-inducing genes which interacts with a specific marker of autophagosomes, i.e., microtubule-associated protein 1 light chain 3 [116, 117]. In an attempt based on siRNA screening, Serine/threonine-protein kinase (ULK1) was identified as a modulator of autophagy pathway [118]. A genetic-based screen finds that disruption of mitochondrial linked genes, protein folding regulators, and signal recognition particle stimulate autophagosomes formation, LysoTracker staining, and autophagy response [119].

In living cells, there is a continuous generation of nascent polypeptides as per need; therefore, it is important to regulate the folding and to promote the regular degradation of misfolded proteins. The mammalian target of rapamycin (mTOR) pathway plays a crucial role in autophagy. Rapamycin is a specific inhibitor of mTOR pathway and retains a high potential to induce autophagy [120]. Treatment of rapamycin reduces the expanded polyglutamine aggregate formation in cells, alleviates neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 suppresses aggregate formation in mouse model of Huntington disease [121, 122]. Everolimus (RAD-001) is another autophagy inducer via mTOR inhibition; stent-based delivery of everolimus reduces atherosclerotic plaques in rabbits [123, 124]. Although the mechanism of autophagy induction has been widely studied, only few candidates have autophagy-inducing efficacy. Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic phytoalexin naturally produced by several plants under attack of pathogens [125]. It has been observed that resveratrol induces autophagy via Sirtuin-1-mediated mechanism improves the life span of various species and acts as anti-aging agent [126129].

Recent advances in the field of autophagy elaborate implication of this mechanism onto various pathological conditions such as cancer, aging, infection, neurodegeneration, and cardiovascular diseases. Therefore, it is important to search the modulators of autophagy pathway; anti-estrogen tamoxifen (TAM) treatment stimulates autophagy in retinal pigment epithelial cell and photoreceptors cells, and activates cell death in human mammary carcinoma MCM7 culture cells [130, 131]. Treatment of spermidine enhances autophagy in many species such as Saccharomyces cerevisiae, D. melanogaster, and C. elegans including mice, and improves their life span [132]. Overall, these studies suggest that autophagy is a critical cellular mechanism through which cell maintains normal homeostasis. Physiological dysfunction in autophagy disturbs the clearance of toxic cellular waste material and initiates several misfolded protein aggregation diseases. To maintain the efficient interior cellular cleaning and to avoid the generation of multifactorial toxic proteins, it is necessary to search new pharmacological inducers based on autophagy and UPS pathways. A better understanding of cross talk between autophagy and UPS will bring new insight as therapeutic strategy for numerous proteotoxic pathological conditions.

Key Questions and Future Prospective

An increasing body of evidence suggests that misfolded protein generation and their aggregation are the basic and fundamental problems of protein conformational disorder and aging-associated diseases. It remains unclear how abnormal or misfolded protein aggregation generates toxic events in cells. Understanding the mechanism of toxicity mediated by damaged or poor protein aggregation is still one of most critical and unsolved problem implicated in numerous neurodegenerative diseases linked with misfolded aggregation. How the aggregation of unwanted noxious proteins leads to massive disturbance in various normal cellular mechanisms is not fully understood. How cells tolerate this serious cytotoxic imbalance, specifically the post-mitotic cells such as neurons? Which genetic and molecular factors cause misfolded proteins formation in cells and how cells develop various defense mechanisms against proteotoxic aggregations remain unsolved. How aging is influenced by aberrant protein aggregation and what kind of relationship exists between aging and non-native protein aggregation are also not very clear.

For findings which can suggest that how cells can inhibit or avoid misfolded protein aggregation and simultaneously induce the degradation of preexisting abnormal proteins, this may open new therapeutic strategies for protein deposition diseases. Much remain to be understood about the proteolytic mechanisms by which an efficient clearance of toxic aggregation-prone proteins can be achieved. As we have shown in Fig. 4 and hypothesize that the detail knowledge of autophagy and UPS intersections may bring new insights into selective misfolded protein degradation. It would be interesting to search new drugs design, pharmacological modulators, or genes which can influence the cross talk between autophagy and UPS functions. Existing mechanisms of misfolded protein aggregation-mediated toxicity suggest that sequestration of numerous critical proteins or factors by abnormal proteins impair the normal functions of cells. Therefore, screening of new molecular agents that can inhibit the sequestration of critical proteins and mitigate the cellular toxicity can serve as valuable cytoprotective agents. How cells define the quality control events during stress conditions and suppress the aggregation of damaged proteins are unsolved aspects. A clear and detailed understanding of cross-linkage of autophagy and UPS pathway may offer a parallel and effective approach for the treatment of misfolded aggregated protein disorders and aging linked diseases.
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Fig. 4

A postulated schematic illustration of “autophagy” and “UPS” coupling in the clearance of misfolded proteins aggregates, which may improve cellular renovation and finally stabilize longevity

Acknowledgments

This work was supported by the Department of Biotechnology, Government of India. AM was supported by Ramalinganswami Fellowship and Innovative Young Biotechnologist Award (IYBA) scheme from the Department of Biotechnology, Government of India. The authors would like to thank Mr. Bharat Pareek and Mr. Rahul Sathya Babu for their technical assistance and the entire lab management during the manuscript preparation. We apologize to various authors whose work could not be included due to space limitations.

Conflict of Interest

The authors declare no conflicts of interest.

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© Springer Science+Business Media New York 2013