alpha-Synuclein modulation of Ca signaling in human neuroblastoma (SH-SY5Y) cells.

J Neurochem. 2009 Oct 5;

Authors: Hettiarachchi NT, Parker A, Dallas ML, Pennington K, Hung CC, Pearson HA, Boyle JP, Robinson P, Peers C

Parkinson's disease (PD) is characterized in part by the presence of alpha-synuclein (alpha-syn) rich intracellular inclusions (Lewy bodies). Mutations and multiplication of the alpha-synuclein gene (SNCA) are associated with familial PD. Since Ca(2+) dyshomeostasis may play an important role in the pathogenesis of PD, we used fluorimetry in fura-2 loaded SH-SY5Y cells to monitor Ca(2+) homeostasis in cells stably transfected with either wild-type alpha-syn, the A53T mutant form, the S129D phosphomimetic mutant or with empty vector (which served as control). Voltage-gated Ca(2+) influx evoked by exposure of cells to 50 mM K(+) was enhanced in cells expressing all three forms of alpha-syn, an effect which was due specifically to increased Ca(2+) entry via L-type Ca(2+) channels. Mobilization of Ca(2+) by muscarine was not strikingly modified by any of the alpha-syn forms, but they all reduced capacitative Ca(2+) entry following store depletion caused either by muscarine or thapsigargin. Emptying of stores with cyclopiazonic acid caused similar rises of [Ca(2+)](i) in all cells tested (with the exception of the S129D mutant), and mitochondrial Ca(2+) content was unaffected by any form of alpha-synuclein. However, only WT alpha-syn transfected cells displayed significantly impaired viability. Our findings suggest that alpha-syn regulates Ca(2+) entry pathways and, consequently, that abnormal alpha-syn levels may promote neuronal damage through dysregulation of Ca(2+) homeostasis.

PMID: 19860837 [PubMed - as supplied by publisher]

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