ALS/FTLD-Linked Mutations in FUS Glycine Residues Cause Accelerated Gelation and Reduced Interactions with Wild-Type FUS

Kevin Rhine, Monika A Makurath, James Liu, Sophie Skanchy, Christian Lopez, Kevin F Catalan, Ye Ma, Charlotte M Fare, James Shorter, Taekjip Ha, Yann R Chemla, Sua Myong

Research output: Contribution to journalArticlepeer-review

Abstract

The RNA-binding protein fused in sarcoma (FUS) can form pathogenic inclusions in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Over 70 mutations in Fus are linked to ALS/FTLD. In patients, all Fus mutations are heterozygous, indicating that the mutant drives disease progression despite the presence of wild-type (WT) FUS. Here, we demonstrate that ALS/FTLD-linked FUS mutations in glycine (G) strikingly drive formation of droplets that do not readily interact with WT FUS, whereas arginine (R) mutants form mixed condensates with WT FUS. Remarkably, interactions between WT and G mutants are disfavored at the earliest stages of FUS nucleation. In contrast, R mutants physically interact with the WT FUS such that WT FUS recovers the mutant defects by reducing droplet size and increasing dynamic interactions with RNA. This result suggests disparate molecular mechanisms underlying ALS/FTLD pathogenesis and differing recovery potential depending on the type of mutation.

Original languageEnglish (US)
Pages (from-to)666-681.e8
JournalMolecular cell
Volume80
Issue number4
DOIs
StatePublished - Nov 19 2020

Keywords

  • Amyotrophic Lateral Sclerosis/genetics
  • Frontotemporal Dementia/genetics
  • Glycine/chemistry
  • Humans
  • Inclusion Bodies
  • Mutation
  • Neuroblastoma/genetics
  • Protein Conformation
  • RNA/chemistry
  • RNA-Binding Protein FUS/chemistry
  • Tumor Cells, Cultured

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