C9orf72 dipeptide repeats impair the assembly, dynamics and function of membrane-less organelles

By Kyung‐Ha Lee, Peipei Zhang, Hong-Joo Kim, Diana M. Mitrea, Mohona Sarkar, Brian D. Freibaum, Jaclyn Cika, Maura Coughlin, James Messing, A. Molliex and 10 more. Cell, 2016

641 citations recorded by the source corpus.

Summary 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.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/3cde57cc71303329ddee2e248cb1ed6cadfd4793

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Citations in the corpus

Tau protein liquid–liquid phase separation can initiate tau aggregation (2018, positive): “However, the functional phase separation of nuclear proteins was shown to be disrupted by C9orf72 GR/PR dipeptide repeats (Lee et al , 2016) and is related to protein aggregation in neuro-degeneration (Schmidt & Rohatgi, 2016).”
Pi-Pi contacts are an overlooked protein feature relevant to phase separation (2018, background): “We note that arginine is likely key for the phase-separation, association and toxicity of C9orf72, which can encode Gly-Arg and Pro-Arg dipeptide repeat sequences (Lee et al., 2016).”
Liquid-Liquid Phase Separation in Disease. (2019, background): “This perturbs their phase separation behavior and impairs the assembly of diverse membraneless organelles, such as stress granules and nucleoli (94).”
Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity (2017, positive): “Therefore, some low-complexity modifications may alter LLPS by disrupting the interactions of negative/positive charged residue patterns (Nott et al , 2015; Lee et al , 2016).”
A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, positive): “The role of tyrosine and arginine residues in driving phase separation of FUS family proteins provides support for recent studies that highlight the importance of cation-p interactions as drivers of phase separation (Nott et al., 2015; Pak et al., 2016; Lee et al., 2016; Boeynaems et al., 2017).”
Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules (2018, background): “SG Composition and Subcellular Distribution Are Affected in iPSC Models of ALS ALS-associated mutant versions of FUS, hnRNPA2/B1, and TIA1, as well as dipeptide repeats (DPRs) derived from an expanded GGGGCC (G4C2) repeat in C9orf72, were recently reported to affect rate and dynamics of SG formation”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “SGs positive for these pathogenic peptides were less dynamic, and moreover, recruited aggregation-prone proteins such as TDP-43 [9, 13].”