Deregulation of autophagy and vesicle trafficking in Parkinson's disease

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease characterized pathologically by the selective loss of dopaminergic neurons in the substantia nigra and the intracellular accumulation of α-synuclein in the Lewy bodies. While the pathogenic mechanisms of PD are poorly understood, many lines of evidence point to a role of altered autophagy and membrane trafficking in the development of the disease. Emerging studies show that connections between the deregulation of autophagy and synaptic vesicle (SV) trafficking may contribute to PD. Here we review the evidence that many PD related-genes have roles in both autophagy and SV trafficking and examine how deregulation of these pathways contributes to PD pathogenesis. This review also discusses recent studies aimed at uncovering the role of PD-linked genes in autophagy-lysosome function.

Keywords: Autophagy; LRRK2; Parkinson’s disease; Synaptic trafficking.

Figure 1. PD linked genes have roles in SV trafficking

Synaptic vesicles release neurotransmitters through highly regulated and tightly coupled rounds of exo- and endocytosis. Many PD-linked genes including α-synuclein, LRRK2, EndoA, synj1, auxilin, syt11, and dynamin are involved in SV cycling, particularly in SV endocytosis. LRRK2 and Parkin, associated with familial PD, are known to post-translationally modify a number of SV endocytosis genes. LRRK2 phosphorylates the SV endocytosis proteins: EndoA, synj1 as well as multiple Rab GTPases that may be involved in SV cycling. Parkin ubiquitinates EndoA, synj1, syt11, and dynamin though more studies are necessary to determine how modification of these proteins influence their function in SV cycling.

Figure 2. Involvement of PD linked genes in SV trafficking and autophagy degradation pathways

Many genes implicated in PD have roles in multiple neuronal trafficking and degradation pathways. For example, LRRK2 and its substrate, EndoA and synj1, are implicated in the dual regulation of SV trafficking and autophagy. The Rab GTPases, also LRRK2 substrates, are likely to regulate trafficking in a number of these pathways but further study of their roles in neurons is necessary. The other PD genes shown here have been implicated in various pathways and require further study to determine their roles in these pathways and how PD-related mutations alter their function. Putative LRRK2 substrates are underlined.