Extended survival of misfolded G85R SOD1-linked ALS mice by transgenic expression of chaperone Hsp110.
Proc Natl Acad Sci U S A
; 113(19): 5424-8, 2016 May 10.
Article
em En
| MEDLINE
| ID: mdl-27114530
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 â¼5.5 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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Taxa de Sobrevida
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Proteínas de Choque Térmico HSP110
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Superóxido Dismutase-1
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Esclerose Lateral Amiotrófica
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Neurônios Motores
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article