Interactions between calcium and alpha-synuclein in neurodegeneration

Abstract

In Parkinson's disease and some atypical Parkinson's syndromes, aggregation of the a-synuclein protein (a-syn) has been linked to neurodegeneration. Many triggers for pathological a-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 a-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 a-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 a-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+, a-syn aggregation and neurotoxicity.