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
Phosphorylation of the α-synuclein (α-syn) protein at Ser129 [P(S129)-α-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)-α-syn plays a central role in the pathogenesis of PD. However, it...
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doaj-e6cfc888a029486e90bd0c862951a4b12021-03-22T12:42:43ZengElsevierNeurobiology of Disease1095-953X2015-06-0178100114Ser129 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 functionKerstin Buck0Natalie Landeck1Ayse Ulusoy2Nour K. Majbour3Omar M.A. El-Agnaf4Deniz Kirik5Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden; Corresponding author.Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, SwedenBrain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, SwedenDepartment of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab EmiratesDepartment of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaBrain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, SwedenPhosphorylation of the α-synuclein (α-syn) protein at Ser129 [P(S129)-α-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)-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 (PLK) 2 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 4 months. 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.http://www.sciencedirect.com/science/article/pii/S0969996115000704α-SynucleinPhosphorylationPolo-like kinaseAdeno-associated vectorParkinson's disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kerstin Buck Natalie Landeck Ayse Ulusoy Nour K. Majbour Omar M.A. El-Agnaf Deniz Kirik |
spellingShingle |
Kerstin Buck Natalie Landeck Ayse Ulusoy Nour K. Majbour Omar M.A. El-Agnaf Deniz Kirik 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 Neurobiology of Disease α-Synuclein Phosphorylation Polo-like kinase Adeno-associated vector Parkinson's disease |
author_facet |
Kerstin Buck Natalie Landeck Ayse Ulusoy Nour K. Majbour Omar M.A. El-Agnaf Deniz Kirik |
author_sort |
Kerstin Buck |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2015-06-01 |
description |
Phosphorylation of the α-synuclein (α-syn) protein at Ser129 [P(S129)-α-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)-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 (PLK) 2 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 4 months. 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. |
topic |
α-Synuclein Phosphorylation Polo-like kinase Adeno-associated vector Parkinson's disease |
url |
http://www.sciencedirect.com/science/article/pii/S0969996115000704 |
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