Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease.
Huntington's disease (HD) is an autosomal dominant neurodegenerative condition caused by expansions of more than 35 uninterrupted CAG repeats in exon 1 of the huntingtin gene. The CAG repeats in HD and the other seven known diseases caused by CAG codon expansions are translated into long polyglutamine tracts that confer a deleterious gain of function on the mutant proteins. Intraneuronal inclusions comprising aggregates of the relevant mutant proteins are found in the brains of patients with HD and related diseases. It is crucial to determine whether the formation of inclusions is directly pathogenic, because a number of studies have suggested that aggregates may be epiphenomena or even protective. Here, we show that fragments of the bacterial chaperone GroEL and the full-length yeast heat shock protein Hsp104 reduce both aggregate formation and cell death in mammalian cell models of HD, consistent with a causal link between aggregation and pathology.
Carmichael
J
J
Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Chatellier
J
J
Woolfson
A
A
Milstein
C
C
Fersht
A R
AR
Rubinsztein
D C
DC
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019556:COS Cells; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D018834:Chaperonin 60 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D016716:PC12 Cells; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D029701:Saccharomyces cerevisiae Proteins; D014162:Transfection
D018834:Chaperonin 60; D005656:Fungal Proteins; D006360:Heat-Shock Proteins; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; C097188:polyglutamine