Journal
BIOMOLECULES
Volume 4, Issue 3, Pages 795-811Publisher
MDPI
DOI: 10.3390/biom4030795
Keywords
alpha-synuclein; Parkinson's disease; calcium; multiple system atrophy; neurodegeneration; oxidative stress
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Funding
- Australian Research Council, Griffith Health Institute
- Clem Jones Foundation
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In Parkinson's disease and some atypical Parkinson's syndromes, aggregation of the alpha-synuclein protein (alpha-syn) has been linked to neurodegeneration. Many triggers for pathological alpha-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic a-syn aggregates. Ca2+-dependent alpha-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote alpha-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson's disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular alpha-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, alpha-syn aggregation and neurotoxicity.
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