Prefoldin Protects Neuronal Cells from Polyglutamine Toxicity by Preventing Aggregation Formation

DOI HANDLE Web Site Web Site Web Site 7 Citations 55 References Open Access

Abstract

Huntington disease is caused by cell death after the expansion of polyglutamine (polyQ) tracts longer than similar to 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.

Journal

  • Journal of Biological Chemistry

    Journal of Biological Chemistry 288 (27), 19958-19972, 2013-07-05

    American Society for Biochemistry Molecular Biology Inc

Citations (7)*help

See more

References(55)*help

See more

Related Projects

See more

Keywords

Report a problem

Back to top