1. A Chemical Chaperone Decouples TDP-43 Disordered Domain Phase Separation from Fibrillation
- Author
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Shih-Chu Jeff Liao, Kyoung-Jae Choi, Mahdi Muhammad Moosa, Adriana Paulucci-Holthauzen, Allan Chris M. Ferreon, Josephine C. Ferreon, and Phoebe S. Tsoi
- Subjects
0301 basic medicine ,Liquid-Liquid Extraction ,Protein aggregation ,Cytoplasmic Granules ,medicine.disease_cause ,Models, Biological ,Protein Aggregation, Pathological ,Biochemistry ,Article ,Methylamines ,03 medical and health sciences ,0302 clinical medicine ,Stress granule ,medicine ,Humans ,Ribonucleoprotein ,Fibrillation ,Mutation ,Chemistry ,Condensation ,DNA-Binding Proteins ,Intrinsically Disordered Proteins ,030104 developmental biology ,Microscopy, Fluorescence ,Ribonucleoproteins ,TDP-43 Proteinopathies ,Unfolded Protein Response ,Unfolded protein response ,Biophysics ,medicine.symptom ,Chemical chaperone ,030217 neurology & neurosurgery ,Molecular Chaperones - Abstract
Ribonucleoprotein (RNP) condensations through liquid-liquid phase separation play vital roles in the dynamic formation-dissolution of stress granules (SGs). These condensations are, however, usually assumed to be linked to pathologic fibrillation. Here, we show that physiologic condensation and pathologic fibrillation of RNPs are independent processes that can be unlinked with the chemical chaperone trimethylamine N-oxide (TMAO). Using the low complexity disordered domain of the archetypical SG-protein TDP-43 as model system, we show that TMAO enhances RNP liquid condensation yet inhibits protein fibrillation. Our results demonstrate effective decoupling of physiologic condensation from pathologic aggregation and suggests that selective targeting of protein fibrillation (without altering condensation) can be employed as therapeutic strategy for RNP aggregation-associated degenerative disorders. [Image: see text]
- Published
- 2018