TY - JOUR
T1 - Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions
AU - Park, Jinyoung
AU - Wu, Yanwei
AU - Shao, Wei
AU - Gendron, Tania F.
AU - van der Spek, Sophie J.F.
AU - Sultanakhmetov, Grigorii
AU - Basu, Avik
AU - Castellanos Otero, Paula
AU - Jones, Caroline J.
AU - Jansen-West, Karen
AU - Daughrity, Lillian M.
AU - Phanse, Sadhna
AU - del Rosso, Giulia
AU - Tong, Jimei
AU - Castanedes-Casey, Monica
AU - Jiang, Lulu
AU - Libera, Jenna
AU - Oskarsson, Björn
AU - Dickson, Dennis W.
AU - Sanders, David W.
AU - Brangwynne, Clifford P.
AU - Emili, Andrew
AU - Wolozin, Benjamin
AU - Petrucelli, Leonard
AU - Zhang, Yong Jie
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/8/29
Y1 - 2023/8/29
N2 - 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.
AB - 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.
KW - CP: Molecular biology
KW - CP: Neuroscience
KW - G3BP1/2
KW - YTHDF proteins
KW - amyotrophic lateral sclerosis
KW - chromosome 9 open reading frame 72
KW - cytoplasmic poly(GR) inclusions
KW - dipeptide repeat proteins
KW - frontotemporal dementia
KW - liquid-liquid phase separation
KW - m6A-modified RNAs
UR - http://www.scopus.com/inward/record.url?scp=85165402597&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85165402597&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2023.112822
DO - 10.1016/j.celrep.2023.112822
M3 - Article
C2 - 37471224
AN - SCOPUS:85165402597
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 8
M1 - 112822
ER -