Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions

Jinyoung Park, Yanwei Wu, Wei Shao, Tania F. Gendron, Sophie J.F. van der Spek, Grigorii Sultanakhmetov, Avik Basu, Paula Castellanos Otero, Caroline J. Jones, Karen Jansen-West, Lillian M. Daughrity, Sadhna Phanse, Giulia del Rosso, Jimei Tong, Monica Castanedes-Casey, Lulu Jiang, Jenna Libera, Björn Oskarsson, Dennis W. Dickson, David W. SandersClifford P. Brangwynne, Andrew Emili, Benjamin Wolozin, Leonard Petrucelli, Yong Jie Zhang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

C9orf72 repeat expansions are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly(GR) proteins are toxic to neurons by forming cytoplasmic inclusions that sequester RNA-binding proteins including stress granule (SG) proteins. However, little is known of the factors governing poly(GR) inclusion formation. Here, we show that poly(GR) infiltrates a finely tuned network of protein-RNA interactions underpinning SG formation. It interacts with G3BP1, the key driver of SG assembly and a protein we found is critical for poly(GR) inclusion formation. Moreover, we discovered that N6-methyladenosine (m6A)-modified mRNAs and m6A-binding YTHDF proteins not only co-localize with poly(GR) inclusions in brains of c9FTD/ALS mouse models and patients with c9FTD, they promote poly(GR) inclusion formation via the incorporation of RNA into the inclusions. Our findings thus suggest that interrupting interactions between poly(GR) and G3BP1 or YTHDF1 proteins or decreasing poly(GR) altogether represent promising therapeutic strategies to combat c9FTD/ALS pathogenesis.

Original languageEnglish (US)
Article number112822
JournalCell Reports
Volume42
Issue number8
DOIs
StatePublished - Aug 29 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

Keywords

  • CP: Molecular biology
  • CP: Neuroscience
  • G3BP1/2
  • YTHDF proteins
  • amyotrophic lateral sclerosis
  • chromosome 9 open reading frame 72
  • cytoplasmic poly(GR) inclusions
  • dipeptide repeat proteins
  • frontotemporal dementia
  • liquid-liquid phase separation
  • m6A-modified RNAs

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