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Title: 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:
 [1];  [1];  [1]; ORCiD logo [2];  [1];  [1];  [1];  [1];  [1];  [3]
  1. St. Jude Children’s Research Hospital, Memphis, TN (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. St. Jude Children’s Research Hospital, Memphis, TN (United States); Univ. of Tennessee Health Sciences Center, Memphis, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1545222
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 74; Journal Issue: 4; Journal ID: ISSN 1097-2765
Publisher:
Cell Press - 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. 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, and Kriwacki, Richard W. Wed . "C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function". United States. doi:10.1016/j.molcel.2019.03.019.
@article{osti_1545222,
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 = {2019},
month = {4}
}

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