Abstract

Introduction

Parkinson's disease is a neurodegenerative disorder characterized by the degeneration of neurons in the substantia nigra pars compacta of the brain. On a cellular level, neuronal loss is accompanied by neurite degeneration and the presence of cytoplasmic inclusions known as Lewy bodies. PD is the most common neurodegenerative movement disorder and the second most common neurodegenerative disease, with the prevalence rising from 1% at age 65 to about 4-5% at age 85 [1]. Most of the PD cases are sporadic, although familial PD with autosomal dominant or autosomal recessive mutations also account for about 5% of all PD cases [2]. PD patients suffer from resting tremor, bradykinesia, muscle rigidity and postural instability. While the deterioration of motor functions observed in PD patients is predominantly attributable to the degeneration of dopaminergic neurons in the substantia nigra, neuron loss in other brain regions, including locus ceruleus and raphe nucleus, are also observed in post-mortem brains of PD patients [3].

Despite the prevalence of the disease, current treatment only ameliorates symptoms by attempting to reverse dopaminergic deficits. Extensive effort has therefore been directed at explicating the pathogenic mechanisms of PD, in hope of identifying targets that would enable reduction of neuronal loss and halting of disease progression. Various pathogenic mechanisms have been associated with neuronal loss in PD, including oxidative stress, mitochondrial dysfunction, protein aggregation and abnormality with the ubiquitin-proteasome pathway [3]. In particular, identification of autosomal dominant and autosomal recessive mutations in cases of familial PD has significantly contributed to our current understanding of the pathogenesis of PD. For example, autosomal dominant A53T and A30P mutation of alpha-synuclein, the main constituent of Lewy bodies, is associated with familial PD [4,5]. Interestingly, mutant alpha-synucleins are more prone to oligomerization [6]. Furthermore, increased gene dosage of alpha-synuclein is associated with certain cases of familial PD [7,8]. These observations point to a pivotal involvement of alpha-synuclein and protein aggregation in the pathogenesis of PD. Presence of protein aggregates in PD brains could also be attributed to deregulation of the ubiquitin-proteasome degradation system. Mutations in Parkin, an ubiquitin E3-ligase, and ubiquitin-C-terminal hydrolase-L1 (UCH-L1), a protein that is involved in the degradation of poly-ubiquitin chains, are both associated with familial PD cases [9,10]. On the other hand, evidence in support of a role of mitochondrial dysfunction in PD came from the identification of mutations in PINK1 and Parkin, both of which have been demonstrated to regulate mitochondrial morphology and function [11,12].

Interestingly, recent studies reveal that deregulation of autophagy is evident in the brains of PD patients [3]. Indeed, the autophagic pathway is increasingly implicated in a number of neurodegenerative diseases [13]. In the following sections, we summarize existing knowledge on the role of autophagy in PD.

The autophagic pathway

Autophagy is traditionally considered as a cellular homeostatic process pivotal for bulk degradation of cytoplasmic contents and organelles. Aside from the ubiquitin-proteasome degradation pathway, which is involved mainly in the breakdown of short-lived proteins, the autophagic pathway represents the other major mechanism by which intracellular proteins are degraded. The autophagic pathway is responsible for the degradation of long-lived proteins, protein aggregates and cytoplasmic organelles [14]. Degradation of proteins and organelles begin with the sequestration of cargo into various vesicles of the autophagic pathway. Based on the mechanisms by which cargos enter the autophagic pathway, 3 different forms of autophagy have been identified: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Macroautophagy is probably the best characterized form of autophagy among the three. Sequestration of cargo begins with the formation of a double-membraned structure known as the autophagosome. Cargos are either sequestered through bulk engulfment of the cytoplasmic content, or through selective targeting. Content of the autophagosomes are then degraded through fusion with lysosomes, leading to the formation of autolysosomes [13,15]. Microautophagy is similar to macroautophagy in that cargos enter the autophagic pathway through direct sequestration of cellular contents, but cargos are sequestered directly into the lysosomes instead of the autophagosomes [13]. On the other hand, CMA is distinct from macroautophagy and microautophagy in several aspects. First of all, instead of sequestration of cargo through bulk engulfment of cytoplasmic contents, proteins destined for CMA usually contain a targeting motif KFERQ and are selectively translocated into the autophagic pathway. Secondly, CMA is predominantly involved in the degradation of soluble proteins. Proteins targeted for CMA are recognized by cytosolic chaperone heat-shock cognate 70 (Hsc70), followed by transportation directly into the lysosomes through association with lysosomes-associated membrane protein 2A (LAMP2A) [13,14]. Figure ​Figure11 summarizes the various types of autophagy.

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Figure 1

Implication of autophagy deregulation in Parkinson's disease (PD). There are 3 types of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). See text for detailed description of the different types of autophagy. Deregulation of both macroautophagy and CMA are implicated in the pathogenesis of PD. CMA is involved in the degradation of soluble wildtype alpha-synuclein, the major constituent of Lewy bodies. Nonetheless, once oligomerized or aggregated, alpha-synuclein is likely degraded by macroautophagy instead of CMA. Interestingly, A53T and A30P mutants of alpha-synuclein are poorly degraded by CMA, but are instead degraded by macroautophagy. Furthermore, the alpha-synuclein mutants inhibit CMA, reducing CMA-mediated degradation of alpha-synuclein and survival factor MEF2D. Concomitant with the inhibition of CMA, overexpression of alpha-synuclein mutants results in a compensatory activation of macroautophagy. Activation of macroautophagy is also evident in cells treated with neurotoxin MPP⁺, a well-established model for Parkinsonism, or following overexpression of GPR37, another protein that is present in Lewy bodies. Finally, recent studies reveal that macroautophagy also plays a role in the turnover of fragmented mitochondria. These observations highlight the potential involvement of the autophagic pathways in the pathogenesis of PD.

Deregulation of the autophagic pathway in PD

Given the role of the autophagic pathway as a degradation system for clearance of aggregated proteins, it is not surprising that autophagic deregulation observed in various neurodegenerative disorders has attracted mounting interests. For example, accumulation of autophagosomes are evident in the brains of Alzheimer's disease patients [13]. Indeed, protein aggregates presents one of the common features in a myriad of neurodegenerative diseases, including the β-amyloid plagues in Alzheimer's disease, mutant huntingtin cytoplasmic inclusions in Huntington's disease, and the alpha-synuclein containing Lewy bodies in PD. While the role of these protein aggregates in the pathogenesis of these disorders remain controversial, it is plausible that removal of protein aggregates through activation of the autophagic pathway would interfere with the potential toxicity of these aggregates, thereby alleviating disease progression. Indeed, accumulating evidence supports a protective role of autophagy through clearance of protein aggregates. For example, reduction of huntingtin aggregates in a model of Huntington's disease through activation of macroautophagy limits neuronal loss and behavioral deficits [16]. Furthermore, knock down of autophagy-related (ATG) genes, molecular players that are pivotal for the induction and execution of macroautophagy, results in neurodegeneration and the presence of cytoplasmic inclusions filled with ubiquitinated proteins [17,18]. These observations suggest that basal level of autophagy is important for the clearance of protein aggregates, and the reduction of cytoplasmic inclusions may be protective against neurodegenerative diseases. Nonetheless, excessive activation of the autophagic pathway has also been associated with cell death [15]. It is therefore pivotal to delineate the precise involvement of autophagy in the pathogenesis of neurodegenerative diseases.

Conclusion

Given the lack of effective treatment targeted at halting disease progression and neuronal loss in PD, advances in the development of novel therapeutic strategy would rely on a better understanding of the pathogenic mechanisms of PD. Mounting evidence suggests that the autophagic pathway is emerging as a key pathway for regulating the pathogenesis of PD. Nonetheless, as mentioned above (Figure ​(Figure1),1), whether activation of autophagy serves a beneficial or detrimental role in PD remains controversial. Since autophagy is part of the cell's homeostatic machinery, basal autophagic activity would undoubtedly be important for minimizing abnormal protein aggregation and for facilitation of organelle turnover. Maintaining autophagic activity at a certain level is particularly important since the level of macroautophagy and CMA are both observed to decrease with age [33]. Development of therapeutic agents that boost autophagic response could thus serve as a strategy to combat protein aggregation in PD, and also in other neurodegenerative diseases with cytoplasmic inclusions. Nonetheless, since excessive activation of the autophagic pathway leads to cell death, designing a drug that would only activate autophagy to a certain optimal extent would be essential, albeit extremely challenging. Ultimately, more physiologically relevant evidence on the activation status of the autophagic pathway in PD patients would be required to determine if activation or suppression of autophagy would be most effective in ameliorating PD symptoms and delaying disease progression. Future studies aiming at resolving the existing controversy would be pivotal in turning these findings into effective treatment against PD.

Abbreviations

ATG: autophagy-related; CMA: chaperone-mediated autophagy; Hsc70: heat-shock cognate 70; LAMP2A: lysosomes-associated membrane protein 2A; PD: Parkinson's disease; UCH-L1: ubiquitin-C-terminal hydrolase-L1.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

ZC and NI wrote, read and approved the final manuscript.

Acknowledgements

References