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.
Highlights
Parkinson’s Disease (PD) is a progressive and a debilitating neurodegenerative disorder which usually occurs in people in their sixth decade with an incidence of around 1% (De Lau and Breteler, 2006)
Some groups have already begun deciphering the points of interaction of some of the risk factors as being at the synapses (Nguyen and Krainc, 2018; Wang et al, 2018) which could well be a starting point of disease pathogenesis and could occur long before clinical symptoms appear
Our understanding of the disease processes that contribute to PD is maturing
Summary
Parkinson’s Disease (PD) is a progressive and a debilitating neurodegenerative disorder which usually occurs in people in their sixth decade with an incidence of around 1% (De Lau and Breteler, 2006). The loss of dopaminergic cells in the substantia nigra leading to a deficit of dopamine in the striatum is the cause of the typical motor features (Fearnley and Lees, 1991). Neuropathological characteristics include dopaminergic cell loss and the presence of Lewy bodies (LBs) and dystrophic neurites termed Lewy neurites (LNs) in the substantia nigra and other brain regions, the main component of which is fibrillar membrane bound forms of α-synuclein. Recent Genome wide association studies (GWAS) have identified further loci across the human genome that are linked to increased lifetime risk for Parkinson’s in idiopathic disease (Kia et al, 2019; Nalls et al, 2019). In this review we will discuss our current understanding of vesicular dysfunction and abnormal protein handling and their role in the causation of PD, bringing together data from Mendelian forms of PD and GWAS nominated genes (Table 1)
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