期刊
NEUROBIOLOGY OF DISEASE
卷 78, 期 -, 页码 100-114出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2015.03.008
关键词
alpha-Synuclein; Phosphorylation; Polo-like kinase; Adeno-associated vector; Parkinson's disease
资金
- Marie Curie FP7 (IEF) [252988]
- Marie Curie FP7 (Neurasyn ITN) [238316]
- European Research Council (TreatPD) [242932]
- Swedish Research Council [2012-2586, 2009-2318]
- Michael J. Fox Foundation
- Swedish Foundation for Strategic Research
- European Research Council (ERC) [242932] Funding Source: European Research Council (ERC)
Phosphorylation of the alpha-synuclein (alpha-syn) protein at Ser129 [P(S129)-alpha-syn] was found to be the most abundant form in intracellular inclusions in brains from Parkinson's disease (PD) patients. This finding suggests that P(S129)-alpha-syn plays a central role in the pathogenesis of PD. However, it is at present unclear whether P(S129)-alpha-syn is pathogenic driving the neurodegenerative process. Rodent studies using neither the phosphomimics of human alpha-syn nor co-expression of human wild-type alpha-syn and kinases phosphorylating alpha-syn at Ser129 gave consistent results. One major concern in interpreting these findings is that human alpha-syn was expressed above physiological levels inducing neurodegeneration in rat nigral neurons. In order to exclude this confounding factor, we took a different approach and increased the phosphorylation level of endogenous alpha-syn. For this purpose, we took advantage of recombinant adeno-associated viral (rAAV) vectors to deliver polo-like kinase (PLK) 2 or PLK3 in the substantia nigra and investigated whether increased levels of P(S129)alpha-syn compromised the function and survival of nigral dopaminergic neurons. Interestingly, we observed that hyperphosphorylated alpha-syn did not induce nigral dopaminergic cell death, as assessed at 1 and 4 months. Furthermore, histological analysis did not show any accumulation of alpha-syn protein or formation of inclusions. Using in vivo microdialysis, we found that the only measurable functional alteration was the depolarisation-induced release of dopamine, while the in vivo synthesis rate of DOPA and dopamine baseline release remained unaltered. Taken together, our results suggest that phosphorylation of alpha-syn at Ser129 does not confer a toxic gain of function per se. (C) 2015 Elsevier Inc. All rights reserved.
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