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Review
. 2020 Jan 8:13:1381.
doi: 10.3389/fnins.2019.01381. eCollection 2019.

Vesicular Dysfunction and the Pathogenesis of Parkinson's Disease: Clues From Genetic Studies

Kirsten Ebanks  1   2 , Patrick A Lewis  3   4 , Rina Bandopadhyay  1   2
Affiliations
Review

Vesicular Dysfunction and the Pathogenesis of Parkinson's Disease: Clues From Genetic Studies

Kirsten Ebanks et al. Front Neurosci. .

Abstract

Parkinson's disease (PD) is a common age-related neurodegenerative disorder with disabling motor symptoms and no available disease modifying treatment. The majority of the PD cases are of unknown etiology, with both genetics and environment playing important roles. Over the past 25 years, however, genetic analysis of patients with familial history of Parkinson's and, latterly, genome wide association studies (GWAS) have provided significant advances in our understanding of the causes of the disease. These genetic insights have uncovered pathways that are affected in both genetic and sporadic forms of PD. These pathways involve oxidative stress, abnormal protein homeostasis, mitochondrial dysfunction, and lysosomal defects. In addition, newly identified PD genes and GWAS nominated genes point toward synaptic changes involving vesicles. This review will highlight the genes that contribute PD risk relating to intracellular vesicle trafficking and their functional consequences. There is still much to investigate on this newly identified and converging pathway of vesicular dynamics and PD, which will aid in better understanding and suggest novel therapeutic strategies for PD patients.

Keywords: Parkinson’s disease; Rab proteins; alpha-synuclein; genetics; genome wide association studies; leucine-rich repeat kinase 2; lysosomal dysfunction; vesicular dysfunction.

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Figures

FIGURE 1
FIGURE 1
Figure depicting the vesicular process with the points of modulation of PD genes and GWAS nominated genes discussed in this review annotated by (1) vesicular fusion, (2) endocytosis, (3) trans golgi network and (4) lysosomes.
FIGURE 2
FIGURE 2
Figure depicting the possible role of the discussed mechanisms as upstream effectors in the generation of α-synuclein aggregation and Lewy body formation. (1) showing the genes involved in the trans-golgi network; (2) in endocytosis and exocytosis; (3) lysosomal genes and (4) the generation of α-synuclein oligomers leading to the formation of (5) Lewy bodies. The precise point at which cytotoxicity occurs in the brain is not clear. Image of α-synuclein fibrils (4) is modified from Li et al. (2018) using a Creative Commons license.
See this image and copyright information in PMC

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