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- W2790799100 abstract "Parkinson's disease (PD) is characterized by intracellular inclusions of aggregated and misfolded α-Synuclein (α-Syn), and the loss of dopaminergic (DA) neurons in the brain. The resulting motor abnormalities mark the progression of PD, while non-motor symptoms can already be identified during early, prodromal stages of disease. Recent studies provide evidence that during this early prodromal phase, synaptic and axonal abnormalities occur before the degenerative loss of neuronal cell bodies. These early phenotypes can be attributed to synaptic accumulation of toxic α-Syn. Under physiological conditions, α-Syn functions in its native conformation as a soluble monomer. However, PD patient brains are characterized by intracellular inclusions of insoluble fibrils. Yet, oligomers and protofibrils of α-Syn have been identified to be the most toxic species, with their accumulation at presynaptic terminals affecting several steps of neurotransmitter release. First, high levels of α-Syn alter the size of synaptic vesicle pools and impair their trafficking. Second, α-Syn overexpression can either misregulate or redistribute proteins of the presynaptic SNARE complex. This leads to deficient tethering, docking, priming and fusion of synaptic vesicles at the active zone (AZ). Third, α-Syn inclusions are found within the presynaptic AZ, accompanied by a decrease in AZ protein levels. Furthermore, α-Syn overexpression reduces the endocytic retrieval of synaptic vesicle membranes during vesicle recycling. These presynaptic alterations mediated by accumulation of α-Syn, together impair neurotransmitter exocytosis and neuronal communication. Although α-Syn is expressed throughout the brain and enriched at presynaptic terminals, DA neurons are the most vulnerable in PD, likely because α-Syn directly regulates dopamine levels. Indeed, evidence suggests that α-Syn is a negative modulator of dopamine by inhibiting enzymes responsible for its synthesis. In addition, α-Syn is able to interact with and reduce the activity of VMAT2 and DAT. The resulting dysregulation of dopamine levels directly contributes to the formation of toxic α-Syn oligomers. Together these data suggest a vicious cycle of accumulating α-Syn and deregulated dopamine that triggers synaptic dysfunction and impaired neuronal communication, ultimately causing synaptopathy and progressive neurodegeneration in Parkinson's disease." @default.
- W2790799100 created "2018-03-29" @default.
- W2790799100 creator A5003473254 @default.
- W2790799100 creator A5086717948 @default.
- W2790799100 date "2018-02-19" @default.
- W2790799100 modified "2023-10-16" @default.
- W2790799100 title "Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's Disease" @default.
- W2790799100 cites W1130374160 @default.
- W2790799100 cites W1270239926 @default.
- W2790799100 cites W1485683953 @default.
- W2790799100 cites W1502551601 @default.
- W2790799100 cites W1527671059 @default.
- W2790799100 cites W1555652578 @default.
- W2790799100 cites W1591639440 @default.
- W2790799100 cites W1597649213 @default.
- W2790799100 cites W1606338704 @default.
- W2790799100 cites W1815242288 @default.
- W2790799100 cites W1860081569 @default.
- W2790799100 cites W1897859562 @default.
- W2790799100 cites W1932752244 @default.
- W2790799100 cites W1965778124 @default.
- W2790799100 cites W1967659552 @default.
- W2790799100 cites W1967905541 @default.
- W2790799100 cites W1968942251 @default.
- W2790799100 cites W1970826466 @default.
- W2790799100 cites W1972565924 @default.
- W2790799100 cites W1972715091 @default.
- W2790799100 cites W1975086853 @default.
- W2790799100 cites W1976345822 @default.
- W2790799100 cites W1977044612 @default.
- W2790799100 cites W1979527613 @default.
- W2790799100 cites W1979591162 @default.
- W2790799100 cites W1979944790 @default.
- W2790799100 cites W1982223225 @default.
- W2790799100 cites W1983609229 @default.
- W2790799100 cites W1989098288 @default.
- W2790799100 cites W1989734945 @default.
- W2790799100 cites W1990473626 @default.
- W2790799100 cites W1992067243 @default.
- W2790799100 cites W1994141638 @default.
- W2790799100 cites W1995737466 @default.
- W2790799100 cites W1996194036 @default.
- W2790799100 cites W1997355141 @default.
- W2790799100 cites W1998879931 @default.
- W2790799100 cites W2000284836 @default.
- W2790799100 cites W2008830477 @default.
- W2790799100 cites W2009556855 @default.
- W2790799100 cites W2009573330 @default.
- W2790799100 cites W2010419635 @default.
- W2790799100 cites W2011473770 @default.
- W2790799100 cites W2011637489 @default.
- W2790799100 cites W2016146578 @default.
- W2790799100 cites W2016742032 @default.
- W2790799100 cites W2017040646 @default.
- W2790799100 cites W2021267750 @default.
- W2790799100 cites W2022628342 @default.
- W2790799100 cites W2022792040 @default.
- W2790799100 cites W2023572125 @default.
- W2790799100 cites W2025922492 @default.
- W2790799100 cites W2026412511 @default.
- W2790799100 cites W2027649342 @default.
- W2790799100 cites W2027822127 @default.
- W2790799100 cites W2028965478 @default.
- W2790799100 cites W2030094319 @default.
- W2790799100 cites W2032014604 @default.
- W2790799100 cites W2033382767 @default.
- W2790799100 cites W2033827101 @default.
- W2790799100 cites W2034147064 @default.
- W2790799100 cites W2036459564 @default.
- W2790799100 cites W2037088901 @default.
- W2790799100 cites W2042920344 @default.
- W2790799100 cites W2043019982 @default.
- W2790799100 cites W2044428616 @default.
- W2790799100 cites W2045277350 @default.
- W2790799100 cites W2046127729 @default.
- W2790799100 cites W2046189898 @default.
- W2790799100 cites W2047565527 @default.
- W2790799100 cites W2052500414 @default.
- W2790799100 cites W2060384627 @default.
- W2790799100 cites W2068288454 @default.
- W2790799100 cites W2070049573 @default.
- W2790799100 cites W2071087722 @default.
- W2790799100 cites W2072989363 @default.
- W2790799100 cites W2073449985 @default.
- W2790799100 cites W2074920372 @default.
- W2790799100 cites W2075793841 @default.
- W2790799100 cites W2075906033 @default.
- W2790799100 cites W2077584190 @default.
- W2790799100 cites W2077910689 @default.
- W2790799100 cites W2081601575 @default.
- W2790799100 cites W2081878678 @default.
- W2790799100 cites W2082425146 @default.
- W2790799100 cites W2084910880 @default.
- W2790799100 cites W2086850124 @default.
- W2790799100 cites W2087482196 @default.
- W2790799100 cites W2091265794 @default.
- W2790799100 cites W2095374280 @default.
- W2790799100 cites W2105725859 @default.
- W2790799100 cites W2108697350 @default.
- W2790799100 cites W2109326232 @default.