Ser129 phosphorylation of endogenous α-synuclein induced by overexpression of polo-like kinases 2 and 3 in nigral dopamine neurons is not detrimental to their survival and function.

Summary, in English

Phosphorylation of the α-synuclein (α-syn) protein at Ser129 [P(S129)-α-] 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)-α-syn plays a central role in the pathogenesis of PD. However, it is at present unclear whether P(S129)-α-syn is pathogenic driving the neurodegenerative process. Rodent studies using neither the phosphomimics of human α-syn nor co-expression of human wild-type α-syn and kinases phosphorylating α-syn at Ser129 gave consistent results. One major concern in interpreting these findings is that human α-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 α-syn. For this purpose, we took advantage of recombinant adeno-associated viral (rAAV) vectors to deliver polo-like kinase 2 (PLK2) or PLK3 in the substantia nigra and investigated whether increased levels of P(S129)-α-syn compromised the function and survival of nigral dopaminergic neurons. Interestingly, we observed that hyperphosphorylated α-syn did not induce nigral dopaminergic cell death, as assessed at 1 and 4months. Furthermore, histological analysis did not show any accumulation of α-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 α-syn at Ser129 does not confer a toxic gain of function per se.

• Författare: Kerstin Buck; Natalie Landeck; Ayse Ulusoy; Nour K Majbour; Omar M A El-Agnaf; Deniz Kirik
• Avdelning/ar: Brain Repair and Imaging in Neural Systems (BRAINS); MultiPark: Multidisciplinary research focused on Parkinson´s disease
• Publiceringsår: 2015
• Språk: Engelska
• Sidor: 100-114
• Publikation/Tidskrift/Serie: Neurobiology of Disease
• Volym: 78
• Issue: Mar 25
• Länkar: http://www.ncbi.nlm.nih.gov/pubmed/25818009?dopt=Abstract; http://dx.doi.org/10.1016/j.nbd.2015.03.008
• Dokumenttyp: Artikel i tidskrift
• Förlag: Elsevier
• Ämne: Neurosciences
• Status: Published
• Forskningsgrupp: Brain Repair and Imaging in Neural Systems (BRAINS)
• ISBN/ISSN/Övrigt: ISSN: 0969-9961