期刊
NEUROSCIENCE LETTERS
卷 611, 期 -, 页码 51-58出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2015.11.023
关键词
alpha-Synuclein; Parkinson's disease; Cytotoxicity; NMDA; Glucocerebrosidase
资金
- Swedish Reseach Council
Progressive accumulation of alpha-synuclein (alpha-syn)-containing protein aggregates throughout the nervous system is a pathological hallmark of Parkinson's disease (PD). The mechanisms whereby alpha-syn exerts neurodegeneration remain to be fully understood. Here we show that overexpression of alpha-syn in transgenic mice leads to increased phosphorylation of glutamate NMDA receptor (NMDAR) subunits NR1 and NR2B in substantia nigra and striatum as well as reduced glucocerebrosidase (GCase) levels. Similarly, molecular studies performed in mouse N2A cells stably overexpressing human alpha-syn ((alpha-syn)N2A) showed that phosphorylation states of the same NMDAR subunits were increased, whereas GCase levels and lysosomal GCase activity were reduced. (alpha-syn)N2A cells showed an increased sensitivity to neurotoxicity towards 6-hydroxydopamine and NMDA. However, wildtype N2A, but not (alpha-syn)nN2A cells, showed a further reduction in viability when co-incubated with 6-hydroxydopamine and the lysosomal inhibitors NH4Cl and leupeptin, suggesting that alpha-syn per se perturbs lysosomal functions. NMDA treatment reduced lysosomal GCase activity to the same extent in (alpha-syn)N2A cells as in wildtype N2A cells, indicating that the (alpha-syn)-syn-dependent difference in NMDA neurotoxicity is unrelated to an altered GCase activity. Nevertheless, these data provide molecular evidence that overexpression of (alpha-syn)-syn simultaneously induces two potential neurotoxic hits by increasing glutamate NMDA receptor phosphorylation, consistent with increased NMDA receptors functionality, and reducing GCase activity. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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