title: Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system.
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.
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. mxilouri@bioacademy.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.forename: Elli
authors.initials: E
authors.lastname: Kyratzi
authors.forename: Pothitos M
authors.initials: PM
authors.lastname: Pitychoutis
authors.forename: Zoi
authors.initials: Z
authors.lastname: Papadopoulou-Daifoti
authors.forename: Celine
authors.initials: C
authors.lastname: Perier
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.forename: Matina
authors.initials: M
authors.lastname: Maniati
authors.forename: Ayse
authors.initials: A
authors.lastname: Ulusoy
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020267:MPTP Poisoning / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000975:Antioxidants; D004298:Dopamine; D018696:Neuroprotective Agents; D043222:Ubiquitin Thiolesterase; C482860:UCHL1 protein, human; C496976:Uchl1 protein, mouse