Journal
CELL
Volume 167, Issue 3, Pages 774-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.10.002
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Funding
- Target ALS
- Packard Center for ALS Research at the Johns Hopkins University
- ALS Association
- American-Lebanese-Syrian Associated Charities
- NIH [R35NS097974]
- HHMI
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Expansion of a hexanucleotide repeat GGGGCC (G(4)C(2)) in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Transcripts carrying (G(4)C(2)) expansions undergo unconventional, non-ATG-dependent translation, generating toxic dipeptide repeat (DPR) proteins thought to contribute to disease. Here, we identify the interactome of all DPRs and find that arginine-containing DPRs, polyGly-Arg (GR) and polyPro-Arg (PR), interact with RNA-binding proteins and proteins with low complexity sequence domains (LCDs) that often mediate the assembly of membrane-less organelles. Indeed, most GR/PR interactors are components of membraneless organelles such as nucleoli, the nuclear pore complex and stress granules. Genetic analysis in Drosophila demonstrated the functional relevance of these interactions to DPR toxicity. Furthermore, we show that GR and PR altered phase separation of LCD-containing proteins, insinuating into their liquid assemblies and changing their material properties, resulting in perturbed dynamics and/or functions of multiple membrane-less organelles.
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