Could a loss of α-synuclein function put dopaminergic neurons at risk? J

Department of Neurology, University of Pittsburgh, BST-South S-510, Pittsburgh, PA 15213, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 07/2004; 89(6):1318-24. DOI: 10.1111/j.1471-4159.2004.02423.x
Source: PubMed


The alpha-synuclein gene is implicated in Parkinson's disease, the symptoms of which occur after a marked loss of substantia nigra dopamine neurons. While the function of alpha-synuclein is not entirely elucidated, one function appears to be as a normal regulatory protein that can bind to and inhibit tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Soluble alpha-synuclein levels may be diminished in Parkinson's disease substantia nigra dopamine neurons both by reduced expression and by alpha-synuclein aggregation as Lewy bodies and Lewy neurites form. The loss of functional alpha-synuclein may then result in dysregulation of tyrosine hydroxylase, dopamine transport and dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and its metabolites are reactive molecules capable of generating highly reactive quinones and reactive oxygen species, a failure to package dopamine into vesicles could cause irreversible damage to cellular macromolecules and contribute to resultant neurotoxicity. This review focuses on how a loss of normal alpha-synuclein function may contribute to the dopamine-related loss of substantia nigra neurons during Parkinson's disease pathogenesis.

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Available from: Ruth G. Perez, Jul 30, 2015
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    • "Melanin synthesis is highly conserved biochemical mechanism throughout the animal kingdom whereby melanin is made from the catecholamine precursors dopa and dopamine, which are synthesized from tyrosine (Prota, 1992). On the other hand, dopamine is known to generate reactive oxygen species (ROS), which can affect the nervous system and overall negatively affect longevity (Perez and Hastings, 2004). Thus, de-pigmentation may be due to induction of a stress response, and may be associated with increased expression of heat shock protein 70 (hsp 70) (Denman et al., 2008; Galvan and Alonso-Alvarez, 2009; Glassman, 2011; Ong et al., 2014). "
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