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J Biol Chem. 2013 Jul 5;288(27):19958-72. doi: 10.1074/jbc.M113.477984. Epub 2013 May 17.

Prefoldin protects neuronal cells from polyglutamine toxicity by preventing aggregation formation.

Author information

1
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, USA.

Abstract

Huntington disease is caused by cell death after the expansion of polyglutamine (polyQ) tracts longer than ∼40 repeats encoded by exon 1 of the huntingtin (HTT) gene. Prefoldin is a molecular chaperone composed of six subunits, PFD1-6, and prevents misfolding of newly synthesized nascent polypeptides. In this study, we found that knockdown of PFD2 and PFD5 disrupted prefoldin formation in HTT-expressing cells, resulting in accumulation of aggregates of a pathogenic form of HTT and in induction of cell death. Dead cells, however, did not contain inclusions of HTT, and analysis by a fluorescence correlation spectroscopy indicated that knockdown of PFD2 and PFD5 also increased the size of soluble oligomers of pathogenic HTT in cells. In vitro single molecule observation demonstrated that prefoldin suppressed HTT aggregation at the small oligomer (dimer to tetramer) stage. These results indicate that prefoldin inhibits elongation of large oligomers of pathogenic Htt, thereby inhibiting subsequent inclusion formation, and suggest that soluble oligomers of polyQ-expanded HTT are more toxic than are inclusion to cells.

KEYWORDS:

Cell Death; Chaperone Chaperonin; Neurodegeneration; Polyglutamine Disease; Protein Aggregation

PMID:
23720755
PMCID:
PMC3707696
DOI:
10.1074/jbc.M113.477984
[Indexed for MEDLINE]
Free PMC Article

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