C9orf72 dipeptide repeats impair the assembly, dynamics and function of membrane-less organelles
| Autor: | Hong Joo Kim, Junmin Peng, Regina-Maria Kolaitis, Diana M. Mitrea, Nam Chul Kim, Jaclyn A Cika, Jennifer Moore, Timothy I. Shaw, James Messing, Peipei Zhang, J. Paul Taylor, Maura Coughlin, Richard W. Kriwacki, Brian A. Maxwell, Jamshid Temirov, Bing Bai, Kyung-Ha Lee, Brian D. Freibaum, Amandine Molliex, Mohona Sarkar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Nucleolus Biology Cytoplasmic Granules Interactome General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Stress granule C9orf72 Organelle Animals Humans Nuclear pore Genetics DNA Repeat Expansion C9orf72 Protein Amyotrophic Lateral Sclerosis Proteins RNA-Binding Proteins Translation (biology) Dipeptides Intracellular Membranes Cell biology 030104 developmental biology Drosophila melanogaster Frontotemporal Dementia Nuclear Pore Peptides 030217 neurology & neurosurgery Function (biology) Cell Nucleolus |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|