Cell Reports (Aug 2023)
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. Sanders,
- Clifford P. Brangwynne,
- Andrew Emili,
- Benjamin Wolozin,
- Leonard Petrucelli,
- Yong-Jie Zhang
Affiliations
- Jinyoung Park
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Yanwei Wu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Wei Shao
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Tania F. Gendron
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55902, USA
- Sophie J.F. van der Spek
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
- Grigorii Sultanakhmetov
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Tokyo, 1920397, Japan
- Avik Basu
- Center for Network Systems Biology, Boston University School of Medicine, Boston, MA 02118, USA
- Paula Castellanos Otero
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Caroline J. Jones
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Karen Jansen-West
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Lillian M. Daughrity
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Sadhna Phanse
- Center for Network Systems Biology, Boston University School of Medicine, Boston, MA 02118, USA
- Giulia del Rosso
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Jimei Tong
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Monica Castanedes-Casey
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Lulu Jiang
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
- Jenna Libera
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
- Björn Oskarsson
- Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
- Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55902, USA
- David W. Sanders
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA
- Clifford P. Brangwynne
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA; Howard Hughes Medical Institute, Princeton, NJ 08544, USA
- Andrew Emili
- Center for Network Systems Biology, Boston University School of Medicine, Boston, MA 02118, USA
- Benjamin Wolozin
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
- Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55902, USA; Corresponding author
- Yong-Jie Zhang
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55902, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 8
p. 112822
Abstract
Summary: 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.
