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Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's disease

Febbraro, Fabia ; Sahin, Gurdal LU ; Farran, Aina ; Soares, Sofia ; Jensen, Poul H. ; Kirik, Deniz LU and Romero-Ramos, Marina (2013) In Neurobiology of Disease 56. p.47-58
Abstract
Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in alpha-synuclein in a rat model for Parkinson's disease using recombinant adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and accordingly the role of S129 phosphorylation in alpha-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioral effects of the S129 modified alpha-synuclein species in vivo. For this purpose, we used two mutated forms of human alpha-synuclein in which the S129 was replaced either with an alanine (S129A), to block... (More)
Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in alpha-synuclein in a rat model for Parkinson's disease using recombinant adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and accordingly the role of S129 phosphorylation in alpha-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioral effects of the S129 modified alpha-synuclein species in vivo. For this purpose, we used two mutated forms of human alpha-synuclein in which the S129 was replaced either with an alanine (S129A), to block phosphorylation, or with an aspartate (S129D), to mimic phosphorylation, and compared them with the wild type alpha-synuclein. This approach was similar in design to previous studies, however our investigation of dopaminergic degeneration also included performing a detailed study of the alpha-synuclein induced pathology in the striatum and the analysis of motor deficits. Our results showed that overexpressing S129D or wild type alpha-synuclein resulted in an accelerated dopaminergic fiber loss as compared with S129A alpha-synuclein. Furthermore, the motor deficit seen in the group treated with the mutant S129D alpha-synuclein appeared earlier than the other two forms of alpha-synuclein. Conversely, S129A alpha-synuclein showed significantly larger pathological alpha-synuclein-positive inclusions, and slower dopaminergic fiber loss, when compared to the other two forms of alpha-synuclein, suggesting a neuroprotective effect of the mutation. When examined at long-term, all three alpha-synuclein forms resulted in pathological accumulations of alpha-synuclein in striatal fibers and dopaminergic cell death in the substantia nigra. Our data show that changes in the S129 residue of alpha-synuclein influence the rate of pathology and neurodegeneration, with an overall deleterious effect of exchanging S129 to a residue mimicking its phosphorylated state. (c) 2013 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alpha-synuclein, Serine phosphorylation, Adeno-associated virus, Striatum
in
Neurobiology of Disease
volume
56
pages
47 - 58
publisher
Elsevier
external identifiers
  • wos:000323853300006
  • scopus:84877352565
  • pmid:23567651
ISSN
0969-9961
DOI
10.1016/j.nbd.2013.03.014
language
English
LU publication?
yes
id
9d8aedfe-e717-423b-bece-5c0cc9226d20 (old id 4170512)
date added to LUP
2016-04-01 10:06:36
date last changed
2020-01-15 01:15:48
@article{9d8aedfe-e717-423b-bece-5c0cc9226d20,
  abstract     = {Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in alpha-synuclein in a rat model for Parkinson's disease using recombinant adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and accordingly the role of S129 phosphorylation in alpha-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioral effects of the S129 modified alpha-synuclein species in vivo. For this purpose, we used two mutated forms of human alpha-synuclein in which the S129 was replaced either with an alanine (S129A), to block phosphorylation, or with an aspartate (S129D), to mimic phosphorylation, and compared them with the wild type alpha-synuclein. This approach was similar in design to previous studies, however our investigation of dopaminergic degeneration also included performing a detailed study of the alpha-synuclein induced pathology in the striatum and the analysis of motor deficits. Our results showed that overexpressing S129D or wild type alpha-synuclein resulted in an accelerated dopaminergic fiber loss as compared with S129A alpha-synuclein. Furthermore, the motor deficit seen in the group treated with the mutant S129D alpha-synuclein appeared earlier than the other two forms of alpha-synuclein. Conversely, S129A alpha-synuclein showed significantly larger pathological alpha-synuclein-positive inclusions, and slower dopaminergic fiber loss, when compared to the other two forms of alpha-synuclein, suggesting a neuroprotective effect of the mutation. When examined at long-term, all three alpha-synuclein forms resulted in pathological accumulations of alpha-synuclein in striatal fibers and dopaminergic cell death in the substantia nigra. Our data show that changes in the S129 residue of alpha-synuclein influence the rate of pathology and neurodegeneration, with an overall deleterious effect of exchanging S129 to a residue mimicking its phosphorylated state. (c) 2013 Elsevier Inc. All rights reserved.},
  author       = {Febbraro, Fabia and Sahin, Gurdal and Farran, Aina and Soares, Sofia and Jensen, Poul H. and Kirik, Deniz and Romero-Ramos, Marina},
  issn         = {0969-9961},
  language     = {eng},
  pages        = {47--58},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's disease},
  url          = {http://dx.doi.org/10.1016/j.nbd.2013.03.014},
  doi          = {10.1016/j.nbd.2013.03.014},
  volume       = {56},
  year         = {2013},
}