Behavioral, Neurochemical, and Histological Characterization of Mice Deficient for Parkin, DJ-1, and Antioxidant Proteins

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Title: Behavioral, Neurochemical, and Histological Characterization of Mice Deficient for Parkin, DJ-1, and Antioxidant Proteins
Author: Seamans, Katherine Webster
Abstract: Parkinson’s disease is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra . The cause of Parkinson’s disease remains uncertain , however , evidence implicates mitochondrial dysfunction and oxidative stress with selective vulnerability of dopaminergic neurons . Although most cases of Parkinson’s disease are sporadic , 5 -10 % of cases are caused by mutations in a single gene . Loss -of -function mutations in parkin and DJ -1 were the first to be linked to recessively inherited parkinsonism . Surprisingly , mice bearing similar loss -of -function mutations in parkin and DJ -1 do not show age -dependent loss of nigral dopaminergic neurons or depletion of dopamine in the striatum . Although the normal cellular functions of Parkin and DJ -1 remain unclear , we hypothesized that Parkin and DJ -1 protect cells from oxidative stress and that loss -of -function mutations in these genes cause neurodegeneration in Parkinson’s disease by rendering cells more sensitive to mitochondrial dysfunction and oxidative stress . We crossed mice deficient for Parkin and DJ -1 with mice deficient for the major mitochondrial antioxidant protein Mn -superoxide dismutase or Cu /Zn -superoxide dismutase . Previous studies have shown that mice with reduced levels of Cu /Zn -superoxide dismutase or Mn -superoxide dismutase are more sensitive to dopaminergic neurotoxins whereas mice with increased levels of superoxide dismutase are more resistant to dopaminergic neurotoxins . We predicted that reducing levels of antioxidant proteins in parkin - / -DJ -1 - / - mice would result in age -dependent nigral cell loss , striatal dopamine depletion or behavioral abnormalities . Characterization of these mice for behavioral abnormalities , neurotransmitter defects and neuropathology , revealed significant behavioral abnormalities in the mutant mice even in the absence of significant changes to dopamine levels in the striatum , dopamine receptor density , or dopaminergic neuron numbers . Aged parkin - / -DJ -1 - / - and Mn -superoxide dismutase triple deficient mice have a surprising enhanced rotorod performance without the presence of an anxiety phenotype or hyperactivity . Cu /Zn -superoxide dismutase and Mn -superoxide dismutase triple deficient mice have elevated levels of dopamine in the striatum , however none of the mice present with nigral cell loss . Levels of D1 -like and D2 -like dopamine receptors in the striatum were unchanged . It is evident from our studies that on a parkin /DJ -1 null background , additional loss of major antioxidant proteins does not lead to a progressive loss of dopaminergic neurons in mice .
URI: http : / /hdl .handle .net /2152 .5 /885
Date: 2011-08-26

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Behavioral, Neurochemical, and Histological Characterization of Mice Deficient for Parkin, DJ-1, and Antioxidant Proteins. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /885 .

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