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Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system

Xilouri, Maria; Kyratzi, Elli; Pitychoutis, Pothitos M.; Papadopoulou-Daifoti, Zoi; Perier, Celine; Vila, Miquel; Maniati, Matina; Ulusoy, Ayse LU ; Kirik, Deniz LU and Park, David S., et al. (2012) In Human Molecular Genetics 21(4). p.874-889
Abstract
Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1... (More)
Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1 protein (gracile axonal dystrophy mice). Our findings show that the lack of wild-type (WT) UCH-L1 does not influence to any significant degree the dopaminergic system at baseline or following injections of the neurotoxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, using a novel intrastriatal adenoviral injection protocol, we have found that mouse nigral neurons retrogradely transduced with S18Y UCH-L1, but not the WT protein, are significantly protected against MPTP toxicity. Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role. (Less)
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publication status
published
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Human Molecular Genetics
volume
21
issue
4
pages
874 - 889
publisher
Oxford University Press
external identifiers
  • wos:000299792800013
  • scopus:84856347615
ISSN
0964-6906
DOI
10.1093/hmg/ddr521
language
English
LU publication?
yes
id
d56fb286-7c1a-4cc4-a92d-60ae2b2775bf (old id 2416084)
date added to LUP
2012-04-02 09:35:20
date last changed
2017-09-24 03:24:45
@article{d56fb286-7c1a-4cc4-a92d-60ae2b2775bf,
  abstract     = {Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1 protein (gracile axonal dystrophy mice). Our findings show that the lack of wild-type (WT) UCH-L1 does not influence to any significant degree the dopaminergic system at baseline or following injections of the neurotoxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, using a novel intrastriatal adenoviral injection protocol, we have found that mouse nigral neurons retrogradely transduced with S18Y UCH-L1, but not the WT protein, are significantly protected against MPTP toxicity. Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role.},
  author       = {Xilouri, Maria and Kyratzi, Elli and Pitychoutis, Pothitos M. and Papadopoulou-Daifoti, Zoi and Perier, Celine and Vila, Miquel and Maniati, Matina and Ulusoy, Ayse and Kirik, Deniz and Park, David S. and Wada, Keiji and Stefanis, Leonidas},
  issn         = {0964-6906},
  language     = {eng},
  number       = {4},
  pages        = {874--889},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system},
  url          = {http://dx.doi.org/10.1093/hmg/ddr521},
  volume       = {21},
  year         = {2012},
}