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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.

Buck, Kerstin LU ; Landeck, Natalie LU ; Ulusoy, Ayse LU ; Majbour, Nour K; El-Agnaf, Omar M A and Kirik, Deniz LU (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)
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author
organization
publishing date
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
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
2015-04-04 16:50:49
date last changed
2017-07-09 03:13:30
@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},
  volume       = {78},
  year         = {2015},
}