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

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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; Kirik, Deniz; Park, David S.; Wada, Keiji; Stefanis, Leonidas.

In: Human Molecular Genetics, Vol. 21, No. 4, 2012, p. 874-889.

Research output: Contribution to journalArticle

Harvard

Xilouri, M, Kyratzi, E, Pitychoutis, PM, Papadopoulou-Daifoti, Z, Perier, C, Vila, M, Maniati, M, Ulusoy, A, Kirik, D, Park, DS, Wada, K & Stefanis, L 2012, 'Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system', Human Molecular Genetics, vol. 21, no. 4, pp. 874-889. https://doi.org/10.1093/hmg/ddr521

APA

Xilouri, M., Kyratzi, E., Pitychoutis, P. M., Papadopoulou-Daifoti, Z., Perier, C., Vila, M., ... Stefanis, L. (2012). Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system. Human Molecular Genetics, 21(4), 874-889. https://doi.org/10.1093/hmg/ddr521

CBE

Xilouri M, Kyratzi E, Pitychoutis PM, Papadopoulou-Daifoti Z, Perier C, Vila M, Maniati M, Ulusoy A, Kirik D, Park DS, Wada K, Stefanis L. 2012. Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system. Human Molecular Genetics. 21(4):874-889. https://doi.org/10.1093/hmg/ddr521

MLA

Vancouver

Xilouri M, Kyratzi E, Pitychoutis PM, Papadopoulou-Daifoti Z, Perier C, Vila M et al. Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system. Human Molecular Genetics. 2012;21(4):874-889. https://doi.org/10.1093/hmg/ddr521

Author

Xilouri, Maria ; Kyratzi, Elli ; Pitychoutis, Pothitos M. ; Papadopoulou-Daifoti, Zoi ; Perier, Celine ; Vila, Miquel ; Maniati, Matina ; Ulusoy, Ayse ; Kirik, Deniz ; Park, David S. ; Wada, Keiji ; Stefanis, Leonidas. / Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 4. pp. 874-889.

RIS

TY - JOUR

T1 - Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system

AU - Xilouri, Maria

AU - Kyratzi, Elli

AU - Pitychoutis, Pothitos M.

AU - Papadopoulou-Daifoti, Zoi

AU - Perier, Celine

AU - Vila, Miquel

AU - Maniati, Matina

AU - Ulusoy, Ayse

AU - Kirik, Deniz

AU - Park, David S.

AU - Wada, Keiji

AU - Stefanis, Leonidas

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddr521

DO - 10.1093/hmg/ddr521

M3 - Article

VL - 21

SP - 874

EP - 889

JO - Human Molecular Genetics

T2 - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

ER -