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Review
. 2019 Feb;42(2):140-149.
doi: 10.1016/j.tins.2018.11.001. Epub 2018 Nov 30.

Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson's Disease

Maria Nguyen  1 , Yvette C Wong  1 , Daniel Ysselstein  1 , Alex Severino  1 , Dimitri Krainc  2
Affiliations
Review

Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson's Disease

Maria Nguyen et al. Trends Neurosci. 2019 Feb.

Abstract

The discovery of genetic forms of Parkinson's disease (PD) has highlighted the importance of the autophagy/lysosomal and mitochondrial/oxidative stress pathways in disease pathogenesis. However, recently identified PD-linked genes, including DNAJC6 (auxilin), SYNJ1 (synaptojanin 1), and the PD risk gene SH3GL2 (endophilin A1), have also highlighted disruptions in synaptic vesicle endocytosis (SVE) as a significant contributor to disease pathogenesis. Additionally, the roles of other PD genes such as LRRK2, PRKN, and VPS35 in the regulation of SVE are beginning to emerge. Here we discuss the recent work on the contribution of dysfunctional SVE to midbrain dopaminergic neurons' selective vulnerability and highlight pathways that demonstrate the interplay of synaptic, mitochondrial, and lysosomal dysfunction in the pathogenesis of PD.

Keywords: Parkinson’s disease; genetics; oxidized dopamine; synaptic vesicle endocytosis; αSynuclein.

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Figures

Figure 1.
Figure 1.. Recently Identified Parkinson’s Disease Genes Play a Role in Synaptic Vesicle Endocytosis (SVE).
The regeneration of synaptic vesicles following neurotransmission involves the concerted effort of various synaptic proteins, some of which have been recently linked to Parkinson’s disease or identified as risk factors for it (indicated in red in the legend, bottom). Clathrin-mediated endocytosis, a common mode of SVE, involves five key steps, illustrated here in the context of dopamine-loaded vesicles. (1) Invagination/constriction: Following the recruitment of adaptor and clathrin-coat proteins to the plasma membrane, endophilin A1 regulates the curvature of the emerging vesicle. Endophilin A1 is also responsible for the recruitment of dynamin to the neck of the clathrin-coated vesicle (CCV). (2) Fission: Dynamin then constricts the neck and mediates CCV fission from the plasma membrane. Endophilin A1 also recruits synaptojanin 1, whose phosphatase activity dephosphorylates synaptic vesicle membrane lipids to release adaptor proteins, allowing auxilin to bind to the CCV. (3) Clathrin uncoating: Auxilin is a cofactor for hsc70, which simulates the removal of the clathrin coat through its ATPase activity. (4) Packaging: Once the clathrin coat is fully removed, dopamine can be packaged into the nascent vesicle. (5) Vesicular dopamine: The dopamine-loaded vesicle is available for the next cycle of neurotransmitter release. Dopamine sequestration inside the vesicle also mitigates elevation of its cytosolic levels and prevents dopamine from becoming oxidized in the cytosol.
Figure 2
Figure 2
Recent work has identified a pathway for cytosolic oxidized dopamine (DA) and αSynuclein accumulation due to dysfunction in synaptic vesicle endocytosis in human-derived dopaminergic neurons [12]. These byproducts can further inhibit mitochondrial function by impairing ATP production and increase reactive oxygen species production via mitochondrially mediated metabolism of cytosolic DA. In addition, they can contribute to lysosomal dysfunction, which may further involve defective proteolytic turnover of synaptic proteins and the accumulation of insoluble protein aggregates. It is conceivable that the convergence of synaptic, mitochondrial, and lysosomal dysfunction may exacerbate cytosolic DA and αSynuclein accumulation and ultimately result in cell death in Parkinson’s disease. Key Figure Deficits in Synaptic Vesicle Endocytosis Potentially Mediate Dopaminergic Neurodegeneration through Intersections with Mitochondrial and Lysosomal Dysfunction
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References

    1. Poewe W et al. (2017) Parkinson disease. Nat. Rev. Dis. Primers 3, 17013. - PubMed
    1. Saheki Y and De Camilli P (2012) Synaptic vesicle endocytosis. Cold Spring Harb. Perspect. Biol 4, a005645. - PMC - PubMed
    1. Kelly BT et al. (2014) Clathrin adaptors. AP2 controls clathrin polymerization with a membrane-activated switch. Science 345, 459–463 - PMC - PubMed
    1. Pechstein A et al. (2015) Vesicle uncoating regulated by SH3–SH3 domain-mediated complex formation between endophilin and intersectin at synapses. EMBO Rep. 16, 232–239 - PMC - PubMed
    1. Verstreken P et al. (2003) Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron 40, 733–748 - PubMed

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