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Review
. 2020:252:271-306.
doi: 10.1016/bs.pbr.2020.02.001. Epub 2020 Mar 16.

Endosomal sorting pathways in the pathogenesis of Parkinson's disease

Lindsey A Cunningham  1 , Darren J Moore  2
Affiliations
Review

Endosomal sorting pathways in the pathogenesis of Parkinson's disease

Lindsey A Cunningham et al. Prog Brain Res. 2020.

Abstract

The identification of Parkinson's disease (PD)-associated genes has created a powerful platform to begin to understand and nominate pathophysiological disease mechanisms. Herein, we discuss the genetic and experimental evidence supporting endolysosomal dysfunction as a major pathway implicated in PD. Well-studied familial PD-linked gene products, including LRRK2, VPS35, and α-synuclein, demonstrate how disruption of different aspects of endolysosomal sorting pathways by disease-causing mutations may manifest into PD-like phenotypes in many disease models. Newly-identified PD-linked genes, including auxilin, synaptojanin-1 and Rab39b, as well as putative risk genes for idiopathic PD (endophilinA1, Rab29, GAK), further support endosomal sorting deficits as being central to PD. LRRK2 may represent a nexus by regulating many distinct features of endosomal sorting, potentially via phosphorylation of key endocytosis machinery (i.e., auxilin, synaptojanin-1, endoA1) and Rab GTPases (i.e., Rab29, Rab8A, Rab10) that function within these pathways. In turn, LRRK2 kinase activity is critically regulated by Rab29 at the Golgi complex and retromer-associated VPS35 at endosomes. Taken together, the known functions of PD-associated gene products, the impact of disease-linked mutations, and the emerging functional interactions between these proteins points to endosomal sorting pathways as a key point of convergence in the pathogenesis of PD.

Keywords: Auxilin; Endolysosomal sorting; Endophilin; GAK; LRRK2; Parkinson's disease; Rab GTPases; Synaptic vesicle endocytosis; Synaptojanin-1; VPS35; α-Synuclein.

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Figures

Figure 1:
Figure 1:
PD-related proteins (bolded) in endolysosomal sorting pathways. A) In the neuronal soma ligands, receptors and transporters are taken up via endocytosis at the plasma membrane. As endosomes mature, lysosomal hydrolases, including cathepsin D, are delivered to the late endosome and lysosome from the trans-Golgi (TGN) as vesicles become more acidic (indicated by deepening purple). The retromer associates with early endosomes to identify cargo for retrograde transport (bold arrows) to the TGN or plasma membrane. Cargo that fail to be retrieved from endosomes accumulate and eventually undergo degradation in lysosomes. LRRK2 is cytoplasmic but is enriched upon different vesicular membranes in a dimeric, active conformation. Certain Rab GTPases are phosphorylated by LRRK2 with Rab29 regulating LRRK2 recruitment to the TGN and stressed lysosomes. PD-linked Rab32 and Rab39b may play a role within the Golgi complex. B) At the synapse, PD-associated proteins are responsible for clathrin-mediated synaptic vesicle endocytosis. 1) EndophilinA1 regulates membrane curvature and recruits dynamin-1 for constriction of plasma membrane buds and 2) eventual fission of clathrin-coated vesicles (CCV). 3) Synaptojanin-1 is recruited by endophilinA1 to dephosphorylate membrane lipids and release adaptor proteins (not shown), allowing auxilin to bind. 4) Auxilin and its cofactor Hsc70 remove the clathrin coat to produce synaptic vesicles that can fuse with endosomes or be loaded with neurotransmitters. Endocytosis represents one potential route for intake of misfolded or aggregated α-synuclein. Created using BioRender.com.
See this image and copyright information in PMC

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