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

• Published in: Scientific reports 2015-10, Vol.5 (1), p.14992-14992, Article 14992
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13; 14; 14/28; 140/133; 631/45/470/2284; 631/92/56; 692/699/375/365; 82; Alzheimer's disease; Amyloid; Amyloid - chemistry; Amyloid - metabolism; Amyloid - ultrastructure; Amyotrophic lateral sclerosis; Animals; Animals, Genetically Modified; Benign; Blotting, Western; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Cell Line, Tumor; Cytotoxicity; Fibrillogenesis; Flow cytometry; Humanities and Social Sciences; Huntingtin; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington's disease; Inclusion bodies; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Microscopy, Confocal; multidisciplinary; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurodegenerative diseases; Neuroprotection; Oligomerization; Pathogenesis; Peptides; Peptides - genetics; Plasmids; Polyglutamine; Protein Aggregates - genetics; Protein Conformation; Proteins; Science; Tacrolimus Binding Protein 1A - genetics; Tacrolimus Binding Protein 1A - metabolism; Trinucleotide repeat diseases; Trinucleotide Repeat Expansion - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep14992

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.