Conformational switch of polyglutamine-expanded huntingtin into benign aggregates leads to neuroprotective effect.

Sun, Chia-Sui; Lee, Chi-Chang; Li, Yi-Ni; Yao-Chen Yang, Sunny; Lin, Chih-Hsiang; Chang, Yi-Che; Liu, Po-Fan; He, Ruei-Yu; Wang, Chih-Hsien; Chen, Wenlung; Chern, Yijuang; Jen-Tse Huang, Joseph

Sun, Chia-Sui; Lee, Chi-Chang; Li, Yi-Ni; Yao-Chen Yang, Sunny; Lin, Chih-Hsiang; Chang, Yi-Che; Liu, Po-Fan; He, Ruei-Yu; Wang, Chih-Hsien; Chen, Wenlung; Chern, Yijuang; Jen-Tse Huang, Joseph.

Afiliación

Sun CS; Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.
Lee CC; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Li YN; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Yao-Chen Yang S; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
Lin CH; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Chang YC; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Liu PF; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
He RY; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Wang CH; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Chen W; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Chern Y; Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Jen-Tse Huang J; Department of Applied Chemistry, National Chiayi University, Chiayi, Taiwan.

Sci Rep ; 5: 14992, 2015 Oct 09.

Article en En | MEDLINE | ID: mdl-26450664

RESUMEN

The abundant accumulation of inclusion bodies containing polyglutamine-expanded mutant huntingtin (mHTT) aggregates is considered as the key pathological event in Huntington's disease (HD). Here, we demonstrate that FKBP12, an isomerase that exhibits reduced expression in HD, decreases the amyloidogenicity of mHTT, interrupts its oligomerization process, and structurally promotes the formation of amorphous deposits. By combining fluorescence-activated cell sorting with multiple biophysical techniques, we confirm that FKBP12 reduces the amyloid property of these ultrastructural-distinct mHTT aggregates within cells. Moreover, the neuroprotective effect of FKBP12 is demonstrated in both cellular and nematode models. Finally, we show that FKBP12 also inhibit the fibrillization process of other disease-related and aggregation-prone peptides. Our results suggest a novel function of FKBP12 in ameliorating the proteotoxicity in mHTT, which may shed light on unraveling the roles of FKBP12 in different neurodegenerative diseases and developing possible therapeutic strategies.

Asunto(s)

Mutación; Proteínas del Tejido Nervioso/genética; Péptidos/genética; Proteína 1A de Unión a Tacrolimus/genética; Expansión de Repetición de Trinucleótido/genética; Amiloide/química; Amiloide/metabolismo; Amiloide/ultraestructura; Animales; Animales Modificados Genéticamente; Western Blotting; Caenorhabditis elegans/genética; Caenorhabditis elegans/metabolismo; Línea Celular Tumoral; Proteína Huntingtina; Enfermedad de Huntington/genética; Enfermedad de Huntington/metabolismo; Proteínas Luminiscentes/genética; Proteínas Luminiscentes/metabolismo; Microscopía Confocal; Proteínas del Tejido Nervioso/química; Proteínas del Tejido Nervioso/metabolismo; Agregado de Proteínas/genética; Conformación Proteica; Proteína 1A de Unión a Tacrolimus/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Expansión de Repetición de Trinucleótido / Proteína 1A de Unión a Tacrolimus / Mutación / Proteínas del Tejido Nervioso Límite: Animals Idioma: En Revista: Sci Rep Año: 2015 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Reino Unido

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