title: p97 Homologs from Caenorhabditis elegans, CDC-48.1 and CDC-48.2, suppress the aggregate formation of huntingtin exon1 containing expanded polyQ repeat.
abstract: 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.
authors.affiliation: Division of Molecular Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishikori
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sakurai
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Esaki
authors.forename: Teru
authors.initials: T
authors.lastname: Ogura
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002417:Cattle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005091:Exons; D018832:Molecular Chaperones / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D013884:Thiosulfate Sulfurtransferase / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D013884:Thiosulfate Sulfurtransferase; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein