Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes

Krishna Puttaparthi, Cezary Wojcik, Bhagya Rajendran, George N. DeMartino, Jeffrey L. Elliott

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Cu,Zn superoxide dismutase (SOD1) mutations cause one form of familial amyotrophic lateral sclerosis by a toxic gain of function that may be related to abnormal protein folding and aggregate formation. However, the processing pathways involved in SOD1 aggregate generation within spinal cord remain unclear. We have now developed an experimental system for studying SOD1 aggregate formation and clearance in intact spinal cord tissue. Here we demonstrate that the formation of SOD1-positive aggregates in G93A SOD1 transgenic mouse spinal cord tissue involves proteasome-mediated proteolysis. Organotypic spinal cord slices from 9-day-old transgenic mice expressing G93A SOD1 develop SOD1 aggregates with proteasome inhibition. In contrast, SOD1 aggregates do not form in spinal cord slices from wild type mice or transgenic mice overexpressing wild type SOD1 following proteasome inhibition. Furthermore, SOD1 aggregate formation within G93A SOD1 spinal cord is both sensitive to small changes in overall proteasome activity and reversible with the restoration of proteasome function. Our results also establish that adult mouse spinal cord exhibits a relative deficiency in proteasome activity compared with non-CNS tissue that may help explain the propensity of spinal cord to form SOD1-positive aggregates.

Original languageEnglish (US)
Pages (from-to)851-860
Number of pages10
JournalJournal of Neurochemistry
Issue number4
StatePublished - Nov 2003


  • Aggregation
  • Aging
  • Amyotrophic lateral sclerosis
  • Motor neuron
  • Proteasome
  • Superoxide dismutase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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