Journal
JOURNAL OF NEUROCHEMISTRY
Volume 105, Issue 6, Pages 2353-2366Publisher
WILEY
DOI: 10.1111/j.1471-4159.2008.05317.x
Keywords
Cu/Zn-superoxide dismutase; Cu/Zn-superoxide dismutase 1; motor neuron disease; protein aggregation; proteolysis; ubiquitin-proteasome pathway
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Funding
- Canadian Institutes of Health Research Funding Source: Medline
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In amyotrophic lateral sclerosis caused by mutations in Cu/Zn-superoxide dismutase (SOD1), altered solubility and aggregation of the mutant protein implicates failure of pathways for detecting and catabolizing misfolded proteins. Our previous studies demonstrated early reduction of proteasome-mediated proteolytic activity in lumbar spinal cord of SOD1(G93A) transgenic mice, tissue particularly vulnerable to disease. The purpose of this study was to identify any underlying abnormalities in proteasomal structure. In lumbar spinal cord of pre-symptomatic mice [postnatal day 45 (P45) and P75], normal levels of structural 20S alpha subunits were incorporated into 20S/26S proteasomes; however, proteasomal complexes separated by native gel electrophoresis showed decreased immunoreactivity with antibodies to beta 3, a structural subunit of the 20S proteasome core, and beta 5, the subunit with chymotrypsin-like activity. This occurred prior to increase in beta 5i immunoproteasomal subunit. mRNA levels were maintained and no association of mutant SOD1 with proteasomes was identified, implicating post-transcriptional mechanisms. mRNAs also were maintained in laser captured motor neurons at a later stage of disease (P100) in which multiple 20S proteins are reduced relative to the surrounding neuropil. Increase in detergent-insoluble, ubiquitinated proteins at P75 provided further evidence of stress on mechanisms of protein quality control in multiple cell types prior to significant motor neuron death.
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