title: Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis.
abstract: Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a familial form of amyotrophic lateral sclerosis (fALS). The present study demonstrated impaired proteasomal function in the lumbar spinal cord of transgenic mice expressing human SOD-1 with the ALS-causing mutation G93A (SOD-1(G93A)) compared to non-transgenic littermates (LM) and SOD-1(WT) transgenic mice. Chymotrypsin-like activity was decreased as early as 45 days of age. By 75 days, chymotrypsin-, trypsin-, and caspase-like activities of the proteasome were impaired, at about 50% of control activity in lumbar spinal cord, but unchanged in thoracic spinal cord and liver. Both total and specific activities of the proteasome were reduced to a similar extent, indicating that a change in proteasome function, rather than a decrease in proteasome levels, had occurred. Similar decreases of total and specific activities of the proteasome were observed in NIH 3T3 cell lines expressing fALS mutants SOD-1(G93A) and SOD-1(G41S), but not in SOD-1(WT) controls. Although overall levels of proteasome were maintained in spinal cord of SOD-1(G93A) transgenic mice, the level of 20S proteasome was substantially reduced in lumbar spinal motor neurons relative to the surrounding neuropil. It is concluded that impairment of the proteasome is an early event and contributes to ALS pathogenesis.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Agar
authors.forename: David M
authors.initials: DM
authors.lastname: Taylor
authors.forename: Sandra
authors.initials: S
authors.lastname: Minotti
authors.forename: Heather D
authors.initials: HD
authors.lastname: Durham
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D008161:Lumbosacral Region; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D009097:Multienzyme Complexes; C000606290:SOD1 protein, human; C109415:SOD1 G93A protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex