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p97 homologs from Caenorhabditis elegans , CDC‐48.1 and CDC‐48.2, suppress the aggregate formation of huntingtin exon1 containing expanded polyQ repeat
Author(s) -
Nishikori Shingo,
Yamanaka Kunitoshi,
Sakurai Toshihiko,
Esaki Masatoshi,
Ogura Teru
Publication year - 2008
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2008.01214.x
Subject(s) - huntingtin , caenorhabditis elegans , biology , protein aggregation , huntingtin protein , chaperone (clinical) , glutamine , biochemistry , microbiology and biotechnology , chemistry , amino acid , gene , mutant , medicine , pathology
Polyglutamine (polyQ)‐expanded proteins are associated with cytotoxicity in some neurodegenerative disorders such as Huntington's disease. We have reported that the aggregation of the polyQ‐expanded protein is partially suppressed by co‐expression of either of two homologs of an AAA chaperone p97, CDC‐48.1 or CDC‐48.2, in Caenorhabditis elegans , but how p97 regulates the aggregation of polyQ‐expanded proteins remains unclear. Here we present direct evidence that CDC‐48.1 and CDC‐48.2 suppress the aggregation of a huntingtin (Htt) exon1 fragment containing an expanded polyQ repeat in vitro . CDC‐48.1 and CDC‐48.2 bound the Htt exon1 fragment directly, and suppressed the formation of SDS‐insoluble aggregates of Htt fragments containing 53 glutamine residues (HttQ53) independently of nucleotides. CDC‐48.1 and CDC‐48.2 also modulated the oligomeric states of HttQ53 during the aggregate formation. In the absence of CDC‐48.1 and CDC‐48.2, HttQ53 formed 70–150 kDa oligomers, whereas 300–500 kDa oligomers as well as 70–150 kDa oligomers accumulated in the presence of CDC‐48.1 and CDC‐48.2. Taken together, these results suggest that p97 plays a protective role in neurodegenerative disorders by directly suppressing the protein aggregation as a molecular chaperone.