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Brain Res. 2013 Oct 25. pii: S0006-8993(13)01425-X. doi: 10.1016/j.brainres.2013.10.034. [Epub ahead of print]

Prefoldin prevents aggregation of α-synuclein.

Author information

1
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan; Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo 060-0810, Japan.
2
Laboratory of Molecular Cell Dynamics, Faculty of Advanced Life Science, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan.
3
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.
4
Graduate School of Agriculture, Hokkaido University, Kita-ku, Sapporo 060-8589, Japan.
5
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan. Electronic address: hiro@pharm.hokudai.ac.jp.

Abstract

Protein aggregation is observed in various neurodegeneration diseases, including Parkinson's disease (PD). Alpha-synuclein, a causative gene product of familial PD, is a major component of large aggregates (inclusion bodies) in PD. Prefoldin, a molecular chaperone comprised of six subunits, PFD1~6, prevents misfolding of newly synthesized nascent polypeptides and also prevents aggregation of protein such as a pathogenic form of Huntingtin, a causative gene product of Huntington disease. In this study, we first found that aggregation of TagRFP-tagged wild-type α-synuclein and its pathogenic mutants, but not that of GFP-tagged α-synuclein, occurred in transfected Neuro-2a cells. The fluorescence of GFP is weakened under the condition of pH 4.5-5.0, and TagRFP is a stable red fluorescence protein under an acidic condition. Aggregated TagRFP-wild-type α-synuclein and its pathogenic mutants in Neuro-2a cells were ubiquitinated and were colocalized with the prefoldin complex in the lysosome under this condition. Furthermore, knockdown of PFD2 and PFD5 disrupted prefoldin formation in α-synuclein-expressing cells, resulting in accumulation of aggregates of wild-type and pathogenic α-synuclein and in induction of cell death. The levels of aggregation and cell death in pathogenic α-synuclein-transfected cells tended to be higher than those in wild-type α-synuclein-transfected cells. These results suggest that prefoldin works as a protective factor in aggregated α-synuclein-induced cell death.

KEYWORDS:

Cell death; Chaperone; Prefoldin; Protein aggregation; α-synuclein

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