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
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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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    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 07/2015; DOI:10.1016/j.fct.2015.06.024 · 2.90 Impact Factor
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    • "Measuring behavior in combination with sensitive bioassays (Bidinosti et al. 2012) may help identify pre-motor PD cases. Although a-Syn is implicated in PD neuropathology, it also contributes to normal physiology by interacting with key regulatory proteins in a chaperone-like manner (Perez and Hastings 2004; Sidhu et al. 2004; Geng et al. 2011). The catalytic subunit of protein phosphatase 2A (PP2A; EC "
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    ABSTRACT: Aging, the main risk factor for Parkinson's disease (PD), stimulates increased α-synuclein levels in substantia nigra pars compacta (SNc). Excess α-synuclein spurs Lewy-like pathology and dysregulates the activity of protein phosphatase 2A (PP2A). PP2A dephosphorylates many neuroproteins, including the catecholamine rate-limiting enzyme, tyrosine hydroxylase (TH). A loss of nigral dopaminergic neurons induces PD movement problems, but before those abnormalities occur, behaviors such as olfactory loss, anxiety, and constipation often manifest. Identifying mouse models with early PD behavioral changes could provide a model in which to test emerging therapeutic compounds. To this end, we evaluated A53T α-synuclein mice for behavior and α-synuclein pathology in olfactory bulb, adrenal gland, and gut. Aging A53T mice exhibited olfactory loss and anxiety that paralleled olfactory and adrenal α-synuclein aggregation. PP2A activity was also diminished in olfactory and adrenal tissues harboring insoluble α-synuclein. Low adrenal PP2A activity co-occurred with TH hyperactivity, making this the first study to link adrenal synucleinopathy to anxiety and catecholamine dysregulation. Aggregated A53T α-synuclein recombinant protein had impaired stimulatory effects on soluble recombinant PP2A. Collectively, the data identify an excellent model in which to screen compounds for their ability to block the spread of α-synuclein pathology associated with premotor stages of PD. This article is protected by copyright. All rights reserved.
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    • "In the presence of reactive oxygen intermediates, NO forms RNSs capable of modifying tyrosine residues in proteins to form 3-nitrotyrosine [93]. In native soluble form, α-synuclein may modulate synaptic plasticity [94] and dopaminergic neurotransmission [95,96]. Aggregation of α-synuclein into protofibrils causes loss in its normal function and impairs dopaminergic neutrotransmission. "
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