title: Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues.
abstract: The mechanisms leading to neurodegeneration in ALS (amyotrophic lateral sclerosis) are not well understood, but cytosolic protein aggregates appear to be common in sporadic and familial ALS as well as transgenic mouse models expressing mutant Cu/Zn superoxide dismutase (SOD1). In this study, we systematically evaluated the presence of these aggregates in three different mouse models (G93A, G85R, and G37R SOD1) and compared these aggregates to those seen in cases of sporadic and familial ALS. Inclusions and loss of motor neurons were observed in spinal cords of all of these three mutant transgenic lines. Since a copper-mediated toxicity hypothesis has been proposed to explain the cytotoxic gain-of-function of mutant SOD1, we sought to determine the involvement of the copper chaperone for SOD1 (CCS) in the formation of protein aggregates. Although all aggregates contained CCS, SOD1 was not uniformly found in the inclusions. Similarly, CCS-positive skein-like inclusions were rarely seen in ALS neurons. These studies do not provide strong evidence for a causal role of CCS in aggregate formation, but they do suggest that protein aggregation is a common event in all animal models of the disease. Selected proteins, such as the glutamate transporter GLT-1, were not typically observed within the inclusions. Most inclusions were positively stained with antibodies recognizing ubiquitin, proteasome, Hsc70 in transgenic lines, and some Hsc70-positive inclusions were detected in sporadic ALS cases. Overall, these observations suggest that inclusions might be sequestered into ubiquitin-proteasome pathway and some chaperone proteins such as Hsc70 may be involved in formation and/or degradation of these inclusions.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Dykes-Hoberg
authors.forename: V C
authors.initials: VC
authors.lastname: Culotta
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: J D
authors.initials: JD
authors.lastname: Rothstein
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003300:Copper / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C114678:CCS protein, human; D002352:Carrier Proteins; C491962:Ccs protein, mouse; D005904:Glial Fibrillary Acidic Protein; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C000606290:SOD1 protein, human; D014452:Ubiquitins; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex