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Citation
Lee, K.H., Zhang, P., Kim, H.J., Mitrea, D.M., Sarkar, M., Freibaum, B.D., Cika, J., Coughlin, M., Messing, J., Molliex, A., Maxwell, B.A., Kim, N.C., Temirov, J., Moore, J., Kolaitis, R.M., Shaw, T.I., Bai, B., Peng, J., Kriwacki, R.W., Taylor, J.P. (2016). C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles.  Cell 167(3): 774--788.e17.
FlyBase ID
FBrf0233795
Publication Type
Research paper
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.
Graphical Abstract
Obtained with permission from Cell Press.
PubMed ID
PubMed Central ID
PMC5079111 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell
    Title
    Cell
    Publication Year
    1974-
    ISBN/ISSN
    0092-8674
    Data From Reference
    Alleles (137)
    Genes (135)
    Human Disease Models (2)
    Natural transposons (2)
    Insertions (1)
    Experimental Tools (2)
    Transgenic Constructs (136)