Τίτλος:
Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © The Author 2011. Published by Oxford University Press. All rights reserved.
Συγγραφείς:
Xilouri, M.
Kyratzi, E.
Pitychoutis, P.M.
Papadopoulou-Daifoti, Z.
Perier, C.
Vila, M.
Maniati, M.
Ulusoy, A.
Kirik, D.
Park, D.S.
Wada, K.
Stefanis, L.
Περιοδικό:
Human Molecular Genetics
Λέξεις-κλειδιά:
1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine; adenovirus vector; beta actin; dopamine; green fluorescent protein; tyrosine 3 monooxygenase; ubiquitin thiolesterase; ubiquitin thiolesterase L1; unclassified drug, animal cell; animal experiment; animal model; animal tissue; antioxidant activity; article; cell loss; controlled study; corpus striatum; dopaminergic system; genetic polymorphism; in vivo study; male; mouse; nerve degeneration; neuroaxonal dystrophy; neuroprotection; nigroneostriatal system; nonhuman; priority journal; protein expression; rat; substantia nigra, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenoviridae; Animals; Antioxidants; Cell Death; Dopamine; Dopaminergic Neurons; Genetic Vectors; Humans; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neostriatum; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Polymorphism, Genetic; Ubiquitin Thiolesterase, Mus
