Extended survival of misfolded G85R SOD1-linked ALS mice by transgenic expression of chaperone Hsp110.
Recent studies have indicated that mammalian cells contain a cytosolic protein disaggregation machinery comprised of Hsc70, DnaJ homologs, and Hsp110 proteins, the last of which acts to accelerate a rate-limiting step of nucleotide exchange of Hsc70. We tested the ability of transgenic overexpression of a Thy1 promoter-driven human Hsp110 protein, HspA4L (Apg1), in neuronal cells of a transgenic G85R SOD1YFP ALS mouse strain to improve survival. Notably, G85R is a mutant version of Cu/Zn superoxide dismutase 1 (SOD1) that is unable to reach native form and that is prone to aggregation, with prominent YFP-fluorescent aggregates observed in the motor neurons of the transgenic mice as early as 1 mo of age. The several-fold overexpression of Hsp110 in motor neurons of these mice was associated with an increased median survival from ∼5.5 to 7.5 mo and increased maximum survival from 6.5 to 12 mo. Improvement of survival was also observed for a G93A mutant SOD1 ALS strain. We conclude that neurodegeneration associated with cytosolic misfolding and aggregation can be ameliorated by overexpression of Hsp110, likely enhancing the function of a cytosolic disaggregation machinery.
Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510; Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Maria
M
Nagy
Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Wayne A
WA
Fenton
Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510; Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Di
D
Li
Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510; Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Krystyna
K
Furtak
Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510; Department of Genetics, Yale School of Medicine, New Haven, CT 06510 arthur.horwich@yale.edu.
Arthur L
AL
Horwich
D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
D050957:HSP110 Heat-Shock Proteins; D018832:Molecular Chaperones; D000072105:Superoxide Dismutase-1
ALS; Hsp110; SOD1; chaperone; survival