A Chemical Chaperone Decouples TDP-43 Disordered Domain Phase Separation from Fibrillation
| Autor: | Shih-Chu Jeff Liao, Kyoung-Jae Choi, Mahdi Muhammad Moosa, Adriana Paulucci-Holthauzen, Allan Chris M. Ferreon, Josephine C. Ferreon, Phoebe S. Tsoi |
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| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | Biochemistry. 57:6822-6826 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | 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] |
| Databáze: | OpenAIRE |
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