C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function
Abstract
Repeat expansion in the C9orf72 gene is the most common cause of the neurodegenerative disorder amyotrophic lateral sclerosis (C9-ALS) and is linked to the unconventional translation of five dipeptide-repeat polypeptides (DPRs). The two enriched in arginine, poly(GR) and poly(PR), infiltrate liquid-like nucleoli, co-localize with the nucleolar protein nucleophosmin (NPM1), and alter the phase separation behavior of NPM1 in vitro. Here, we show that poly(PR) DPRs bind tightly to a long acidic tract within the intrinsically disordered region of NPM1, altering its phase separation with nucleolar partners to the extreme of forming large, soluble complexes that cause droplet dissolution in vitro. In cells, poly(PR) DPRs disperse NPM1 from nucleoli and entrap rRNA in static condensates in a DPR-length-dependent manner. Here, we propose that R-rich DPR toxicity involves disrupting the role of phase separation by NPM1 in organizing ribosomal proteins and RNAs within the nucleolus.
- Authors:
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1619327
- Alternate Identifier(s):
- OSTI ID: 1545222
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Published Article
- Journal Name:
- Molecular Cell
- Additional Journal Information:
- Journal Name: Molecular Cell Journal Volume: 74 Journal Issue: 4; Journal ID: ISSN 1097-2765
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; nucleophosmin; dipeptide repeat; DPR; C9orf72; ALS; liquid-liquid phase separation; nucleolus; ribosome; RNA; intrinsically disordered region
Citation Formats
White, Michael R., Mitrea, Diana M., Zhang, Peipei, Stanley, Christopher B., Cassidy, Devon E., Nourse, Amanda, Phillips, Aaron H., Tolbert, Michele, Taylor, J. Paul, and Kriwacki, Richard W. C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function. United States: N. p., 2019.
Web. doi:10.1016/j.molcel.2019.03.019.
White, Michael R., Mitrea, Diana M., Zhang, Peipei, Stanley, Christopher B., Cassidy, Devon E., Nourse, Amanda, Phillips, Aaron H., Tolbert, Michele, Taylor, J. Paul, & Kriwacki, Richard W. C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function. United States. https://doi.org/10.1016/j.molcel.2019.03.019
White, Michael R., Mitrea, Diana M., Zhang, Peipei, Stanley, Christopher B., Cassidy, Devon E., Nourse, Amanda, Phillips, Aaron H., Tolbert, Michele, Taylor, J. Paul, and Kriwacki, Richard W. Wed .
"C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function". United States. https://doi.org/10.1016/j.molcel.2019.03.019.
@article{osti_1619327,
title = {C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function},
author = {White, Michael R. and Mitrea, Diana M. and Zhang, Peipei and Stanley, Christopher B. and Cassidy, Devon E. and Nourse, Amanda and Phillips, Aaron H. and Tolbert, Michele and Taylor, J. Paul and Kriwacki, Richard W.},
abstractNote = {Repeat expansion in the C9orf72 gene is the most common cause of the neurodegenerative disorder amyotrophic lateral sclerosis (C9-ALS) and is linked to the unconventional translation of five dipeptide-repeat polypeptides (DPRs). The two enriched in arginine, poly(GR) and poly(PR), infiltrate liquid-like nucleoli, co-localize with the nucleolar protein nucleophosmin (NPM1), and alter the phase separation behavior of NPM1 in vitro. Here, we show that poly(PR) DPRs bind tightly to a long acidic tract within the intrinsically disordered region of NPM1, altering its phase separation with nucleolar partners to the extreme of forming large, soluble complexes that cause droplet dissolution in vitro. In cells, poly(PR) DPRs disperse NPM1 from nucleoli and entrap rRNA in static condensates in a DPR-length-dependent manner. Here, we propose that R-rich DPR toxicity involves disrupting the role of phase separation by NPM1 in organizing ribosomal proteins and RNAs within the nucleolus.},
doi = {10.1016/j.molcel.2019.03.019},
journal = {Molecular Cell},
number = 4,
volume = 74,
place = {United States},
year = {Wed May 01 00:00:00 EDT 2019},
month = {Wed May 01 00:00:00 EDT 2019}
}
https://doi.org/10.1016/j.molcel.2019.03.019
Web of Science
Works referencing / citing this record:
Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders
journal, January 2020
- Boivin, Manon; Pfister, Véronique; Gaucherot, Angeline
- The EMBO Journal, Vol. 39, Issue 4
Primary Neurons and Differentiated NSC-34 Cells Are More Susceptible to Arginine-Rich ALS Dipeptide Repeat Protein-Associated Toxicity than Non-Differentiated NSC-34 and CHO Cells
journal, December 2019
- Gill, Anna L.; Wang, Monica Z.; Levine, Beth
- International Journal of Molecular Sciences, Vol. 20, Issue 24