title: 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.
authors.affiliation: Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Institute of Chemistry, Academia Sinica, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Sui
authors.initials: CS
authors.lastname: Sun
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Chi-Chang
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Ni
authors.initials: YN
authors.lastname: Li
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Sunny
authors.initials: S
authors.lastname: Yao-Chen Yang
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Che
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Po-Fan
authors.initials: PF
authors.lastname: Liu
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Ruei-Yu
authors.initials: RY
authors.lastname: He
authors.affiliation: Department of Applied Chemistry, National Chiayi University, Chiayi, Taiwan.
authors.forename: Chih-Hsien
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Applied Chemistry, National Chiayi University, Chiayi, Taiwan.
authors.forename: Wenlung
authors.initials: W
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jen-Tse Huang
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics*; D066329:Protein Aggregates / Q000235:genetics; D011487:Protein Conformation; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics* / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000682:Amyloid; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D066329:Protein Aggregates; C097188:polyglutamine; D022061:Tacrolimus Binding Protein 1A