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Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle.
Lotz, Gregor P; Legleiter, Justin; Aron, Rebecca; Mitchell, Emily J; Huang, Shao-Yi; Ng, Cheping; Glabe, Charles; Thompson, Leslie M; Muchowski, Paul J.
Afiliação
  • Lotz GP; Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
J Biol Chem ; 285(49): 38183-93, 2010 Dec 03.
Article em En | MEDLINE | ID: mdl-20864533
ABSTRACT
Inclusion bodies of aggregated mutant huntingtin (htt) fragments are a neuropathological hallmark of Huntington disease (HD). The molecular chaperones Hsp70 and Hsp40 colocalize to inclusion bodies and are neuroprotective in HD animal models. How these chaperones suppress mutant htt toxicity is unclear but might involve direct effects on mutant htt misfolding and aggregation. Using size exclusion chromatography and atomic force microscopy, we found that mutant htt fragments assemble into soluble oligomeric species with a broad size distribution, some of which reacted with the conformation-specific antibody A11. Hsp70 associated with A11-reactive oligomers in an Hsp40- and ATP-dependent manner and inhibited their formation coincident with suppression of caspase 3 activity in PC12 cells. Thus, Hsp70 and Hsp40 (DNAJB1) dynamically target specific subsets of soluble oligomers in a classic ATP-dependent reaction cycle, supporting a pathogenic role for these structures in HD.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Proteínas Nucleares / Corpos de Inclusão / Trifosfato de Adenosina / Proteínas de Choque Térmico HSP70 / Proteínas de Choque Térmico HSP40 / Multimerização Proteica / Proteínas do Tecido Nervoso Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Proteínas Nucleares / Corpos de Inclusão / Trifosfato de Adenosina / Proteínas de Choque Térmico HSP70 / Proteínas de Choque Térmico HSP40 / Multimerização Proteica / Proteínas do Tecido Nervoso Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Estados Unidos