title: C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles.
abstract: 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.
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Kyung-Ha
authors: KH
authors: Lee
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Peipei
authors: P
authors: Zhang
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Hong Joo
authors: HJ
authors: Kim
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Diana M
authors: DM
authors: Mitrea
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Mohona
authors: M
authors: Sarkar
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Brian D
authors: BD
authors: Freibaum
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jaclyn
authors: J
authors: Cika
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Maura
authors: M
authors: Coughlin
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: James
authors: J
authors: Messing
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Amandine
authors: A
authors: Molliex
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Brian A
authors: BA
authors: Maxwell
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Nam Chul
authors: NC
authors: Kim
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jamshid
authors: J
authors: Temirov
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jennifer
authors: J
authors: Moore
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Regina-Maria
authors: RM
authors: Kolaitis
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Timothy I
authors: TI
authors: Shaw
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Bing
authors: B
authors: Bai
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Junmin
authors: J
authors: Peng
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN 38105, USA.
authors: Richard W
authors: RW
authors: Kriwacki
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: jpaul.taylor@stjude.org.
authors: J Paul
authors: JP
authors: Taylor
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000073885:C9orf72 Protein; D002466:Cell Nucleolus / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D042622:DNA Repeat Expansion; D004151:Dipeptides / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D022022:Nuclear Pore / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D010455:Peptides; D011506:Proteins; D016601:RNA-Binding Proteins; C011083:polyproline; C015462:polyarginine; C011080:polyglycine
keywords: C9ORF72; amyotrophic lateral sclerosis; dipeptide repeat; membrane-less organelle; nucleolus; phase separation; stress granule