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.
(2015) In Neurobiology of Disease 78(Mar 25). p.100-114- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5257442
- author
- Buck, Kerstin LU ; Landeck, Natalie LU ; Ulusoy, Ayse LU ; Majbour, Nour K ; El-Agnaf, Omar M A and Kirik, Deniz LU
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Neurobiology of Disease
- volume
- 78
- issue
- Mar 25
- pages
- 100 - 114
- publisher
- Elsevier
- external identifiers
-
- pmid:25818009
- wos:000354419800011
- scopus:84926628090
- pmid:25818009
- ISSN
- 0969-9961
- DOI
- 10.1016/j.nbd.2015.03.008
- language
- English
- LU publication?
- yes
- id
- f89d1efb-4de0-44c4-9efb-84953d34f428 (old id 5257442)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25818009?dopt=Abstract
- date added to LUP
- 2016-04-01 10:28:28
- date last changed
- 2022-04-27 22:30:43
@article{f89d1efb-4de0-44c4-9efb-84953d34f428,
abstract = {{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.}},
author = {{Buck, Kerstin and Landeck, Natalie and Ulusoy, Ayse and Majbour, Nour K and El-Agnaf, Omar M A and Kirik, Deniz}},
issn = {{0969-9961}},
language = {{eng}},
number = {{Mar 25}},
pages = {{100--114}},
publisher = {{Elsevier}},
series = {{Neurobiology of Disease}},
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.}},
url = {{http://dx.doi.org/10.1016/j.nbd.2015.03.008}},
doi = {{10.1016/j.nbd.2015.03.008}},
volume = {{78}},
year = {{2015}},
}