title: Differential effects of mutant SOD1 on protein structure of skeletal muscle and spinal cord of familial amyotrophic lateral sclerosis: role of chaperone network.
abstract: Protein misfolding is considered to be a potential contributing factor for motor neuron and muscle loss in diseases like Amyotrophic lateral sclerosis (ALS). Several independent studies have demonstrated using over-expressed mutated Cu/Zn-superoxide dismutase (mSOD1) transgenic mouse models which mimic familial ALS (f-ALS), that both muscle and motor neurons undergo degeneration during disease progression. However, it is unknown whether protein conformation of skeletal muscle and spinal cord is equally or differentially affected by mSOD1-induced toxicity. It is also unclear whether heat shock proteins (Hsp's) differentially modulate skeletal muscle and spinal cord protein structure during ALS disease progression. We report three intriguing observations utilizing the f-ALS mouse model and cell-free in vitro system; (i) muscle proteins are equally sensitive to misfolding as spinal cord proteins despite the presence of low level of soluble and absence of insoluble G93A protein aggregate, unlike in spinal cord, (ii) Hsp's levels are lower in muscle compared to spinal cord at any stage of the disease, and (iii) G93ASOD1 enzyme-induced toxicity selectively affects muscle protein conformation over spinal cord proteins. Together, these findings strongly suggest that differential chaperone levels between skeletal muscle and spinal cord may be a critical determinant for G93A-induced protein misfolding in ALS.
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, United States.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Wei
authors.forename: Arunabh
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Hamilton
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Jernigan
authors.forename: Asish R
authors.initials: AR
authors.lastname: Chaudhuri
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity; D013116:Spinal Cord / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid dipotassium salt; BisANS; Familial ALS; Heat shock proteins; Hsp; Mutant SOD1; Protein conformation; Surface hydrophobicity; f-ALS; familial Amyotrophic lateral sclerosis; heat shock protein