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

• Published in: Trends in neurosciences (Regular ed.) Vol. 42; no. 2; pp. 140 - 149
• Main Authors: Nguyen, Maria, Wong, Yvette C., Ysselstein, Daniel, Severino, Alex, Krainc, Dimitri
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2019
• Subjects: alpha-Synuclein - metabolism; Animals; Autophagy; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Endocytosis; Genetic Predisposition to Disease; genetics; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; Lysosomes - metabolism; Mitochondria - metabolism; Oxidative Stress; oxidized dopamine; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson’s disease; synaptic vesicle endocytosis; Synaptic Vesicles - metabolism; αSynuclein; αSynuclein; oxidized dopamine; synaptic vesicle endocytosis; genetics; Parkinson’s disease
• ISSN: 0166-2236; 1878-108X; 1878-108X
• DOI: 10.1016/j.tins.2018.11.001

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. Emerging genetic and mechanistic studies link synaptic, mitochondrial, and lysosomal dysfunction as major contributors to the degeneration of midbrain dopaminergic neurons. Recently, endocytic genes (DNAJC6, SYNJ1, and SH3GL2) have been linked to Parkinson’s disease pathogenesis or identified as a risk factor for the disease, implicating a role for impaired synaptic vesicle endocytosis (SVE) in neurodegeneration. Among the modifiers of proteins involved in SVE are LRRK2 and parkin. LRRK2’s and parkin’s involvement in this context is through their phosphorylation and ubiquitination actions, respectively. Dysfunction in SVE in dopaminergic neurons can lead to increased levels of unpackaged, cytosolic DA that is subject to oxidation and pathogenic downstream effects.