Role of the endolysosomal system in Parkinson's disease
Autor: | Sreeganga S. Chandra, John E. Lee, D.J. Vidyadhara |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Parkinson's disease PINK1 Nerve Tissue Proteins Endosomes Biology Biochemistry Membrane Fusion Parkin Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Risk Factors Mitophagy medicine Autophagy Humans Transport Vesicles Genetic Association Studies Parkinson Disease medicine.disease LRRK2 Axons Corpus Striatum Endocytosis Retromer complex Substantia Nigra 030104 developmental biology Proteostasis Mutation Synuclein Lysosomes Neuroscience 030217 neurology & neurosurgery Forecasting |
Zdroj: | J Neurochem |
ISSN: | 1471-4159 |
Popis: | Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting 1-1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E-L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin-mediated synaptic endocytosis, an integral part of the neuronal E-L system, is probably the main early target as evident in auxilin, RME-8, and synaptojanin-1 mutations that cause PD. Autophagy, another important pathway in the E-L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life-time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi-compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α-synuclein and LRRK2, key proteins involved in PD, function in different steps of the E-L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E-L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue "Synuclein". |
Databáze: | OpenAIRE |
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