Unknown

Dataset Information

0

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


ABSTRACT: 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.

SUBMITTER: Sun CS 

PROVIDER: S-EPMC4598856 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Sun Chia-Sui CS   Lee Chi-Chang CC   Li Yi-Ni YN   Yao-Chen Yang Sunny S   Lin Chih-Hsiang CH   Chang Yi-Che YC   Liu Po-Fan PF   He Ruei-Yu RY   Wang Chih-Hsien CH   Chen Wenlung W   Chern Yijuang Y   Jen-Tse Huang Joseph J  

Scientific reports 20151009


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 techn  ...[more]

Similar Datasets

| S-EPMC4016121 | biostudies-literature
| S-EPMC151354 | biostudies-literature
2012-06-19 | GSE38002 | GEO
| S-EPMC5479704 | biostudies-literature
2012-06-18 | E-GEOD-38002 | biostudies-arrayexpress
| S-EPMC3137094 | biostudies-literature
2012-06-19 | GSE38001 | GEO
| S-EPMC6920524 | biostudies-literature
2012-06-18 | E-GEOD-38001 | biostudies-arrayexpress
2012-06-19 | GSE38000 | GEO