title: Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes.
abstract: 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.
authors: Department of Neurology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Krishna
authors: K
authors: Puttaparthi
authors: Cezary
authors: C
authors: Wojcik
authors: Bhagya
authors: B
authors: Rajendran
authors: George N
authors: GN
authors: DeMartino
authors: Jeffrey L
authors: JL
authors: Elliott
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D046988:Proteasome Endopeptidase Complex; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex