Abstract
R-rich dipeptide repeat proteins (DRPs: poly(PR) and poly(GR)), encoded by a hexanucleotide expansion in the C9ORF72 gene, induce neurodegeneration in amyotrophic lateral sclerosis (ALS). Although R-rich DRPs undergo liquid-liquid phase separation (LLPS), which affects multiple biological processes, mechanisms underlying LLPS of DRPs remain elusive. Here, using in silico, in vitro, and in vivo methods, we determined that the distribution of charged Arg residues regulates the complex coacervation with anionic peptides and nucleic acids. Proteomic analyses revealed that alternate Arg distribution in DRPs facilitates entrapment of proteins with acidic motifs via LLPS. Protein translation and mobility of nucleolar nucleophosmin (NPM1) were impaired by poly(PR) with an alternate charge distribution but not by poly(PR) variants with a consecutive charge distribution. We propose that the pathogenicity of DRPs is mediated bydisturbance of proteins through entrapment in the phase-separated droplets via sequence-controlled multivalent protein-protein interactions.
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