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Proc Natl Acad Sci U S A. 2016 May 10;113(19):5424-8. doi: 10.1073/pnas.1604885113. Epub 2016 Apr 25.

Extended survival of misfolded G85R SOD1-linked ALS mice by transgenic expression of chaperone Hsp110.

Author information

1
Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510; Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
2
Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
3
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.

Abstract

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.

KEYWORDS:

ALS; Hsp110; SOD1; chaperone; survival

PMID:
27114530
PMCID:
PMC4868459
DOI:
10.1073/pnas.1604885113
[Indexed for MEDLINE]
Free PMC Article

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