Journal
MOLECULAR CELL
Volume 82, Issue 5, Pages 969-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2022.01.018
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Funding
- National Institutes of Health [F31-NS113439, T32-GM007231, T32-GM080189, F31-NS111870, T32-GM008275, R21-NS090205, R01-GM104135, RF1-AG071326, RF1-NS113636]
- National Science Foundation [PHY-1430124]
- Johns Hopkins Provost's Undergraduate Research Award
- G. Harold and Leila Y. Mathers Charitable Foundation
- Target ALS
- ALSA
- Packard Center for ALS Research
- Johns Hopkins Discovery Award
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This study demonstrates how Poly(ADP-ribose) (PAR) triggers condensation of FUS at a low concentration, and reveals a different mode of interaction between PAR and FUS compared to RNA.
Poly(ADP-ribose) (PAR) is an RNA-like polymer that regulates an increasing number of biological processes. Dysregulation of PAR is implicated in neurodegenerative diseases characterized by abnormal protein aggregation, including amyotrophic lateral sclerosis (ALS). PAR forms condensates with FUS, an RNA-binding protein linked with ALS, through an unknown mechanism. Here, we demonstrate that a strikingly low concentration of PAR (1 nM) is sufficient to trigger condensation of FUS near its physiological concentration (1 mu M), which is three orders of magnitude lower than the concentration at which RNA induces condensation (1 mu M). Unlike RNA, which associates with FUS stably, PAR interacts with FUS transiently, triggering FUS to oligomerize into condensates. Moreover, inhibition of a major PAR-synthesizing enzyme, PARP5a, diminishes FUS condensation in cells. Despite their structural similarity, PAR and RNA co-condense with FUS, driven by disparate modes of interaction with FUS. Thus, we uncover a mechanism by which PAR potently seeds FUS condensation.
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