C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles

Kyung Ha Lee, Peipei Zhang, Hong Joo Kim, Diana M. Mitrea, Mohona Sarkar, Brian D. Freibaum, Jaclyn Cika, Maura Coughlin, James Messing, Amandine Molliex, Brian A. Maxwell, Nam Chul Kim, Jamshid Temirov, Jennifer Moore, Regina Maria Kolaitis, Timothy I. Shaw, Bing Bai, Junmin Peng, Richard W. Kriwacki, J. Paul Taylor

Research output: Contribution to journalArticlepeer-review

374 Scopus citations


Expansion of a hexanucleotide repeat GGGGCC (G4C2) in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Transcripts carrying (G4C2) 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 membrane-less 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.

Original languageEnglish (US)
Pages (from-to)774-788.e17
Issue number3
StatePublished - Oct 20 2016

Bibliographical note

Funding Information:
We thank the Bloomington Drosophila Stock Center, the VDRC Stock Center for fly lines, and the Proteomics and Cell and Tissue Imaging Centers at St. Jude Children’s Research Hospital for assistance. We also thank Natalia Nedelsky for editorial assistance. This work was supported by grants from Target ALS, The Packard Center for ALS Research at the Johns Hopkins University, the ALS Association, the American-Lebanese-Syrian Associated Charities, NIH grant R35NS097974, and HHMI to J.P.T. J.P.T. is a consultant for Inception Biosciences.

Publisher Copyright:
© 2016 Elsevier Inc.


  • C9ORF72
  • amyotrophic lateral sclerosis
  • dipeptide repeat
  • membrane-less organelle
  • nucleolus
  • phase separation
  • stress granule


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