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

doi:10.1016/j.celrep.2023.112822

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 journal › Article › peer-review

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 language	English (US)
Article number	112822
Journal	Cell reports
Volume	42
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2023.112822
State	Published - Aug 29 2023

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.112822

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Park, J., Wu, Y., Shao, W., Gendron, T. F., van der Spek, S. J. F., Sultanakhmetov, G., Basu, A., Castellanos Otero, P., Jones, C. J., Jansen-West, K., Daughrity, L. M., Phanse, S., del Rosso, G., Tong, J., Castanedes-Casey, M., Jiang, L., Libera, J., Oskarsson, B., Dickson, D. W., ... Zhang, Y. J. (2023). Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions. Cell reports, 42(8), Article 112822. https://doi.org/10.1016/j.celrep.2023.112822

Park, J, Wu, Y, Shao, W, Gendron, TF, van der Spek, SJF, Sultanakhmetov, G, Basu, A, Castellanos Otero, P, Jones, CJ, Jansen-West, K, Daughrity, LM, Phanse, S, del Rosso, G, Tong, J, Castanedes-Casey, M, Jiang, L, Libera, J, Oskarsson, B , Dickson, DW, Sanders, DW, Brangwynne, CP, Emili, A, Wolozin, B, Petrucelli, L & Zhang, YJ 2023, 'Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions', Cell reports, vol. 42, no. 8, 112822. https://doi.org/10.1016/j.celrep.2023.112822

@article{95df95e7c9114f6a82dacab80b239e3f,

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

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.",

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",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = aug,

day = "29",

doi = "10.1016/j.celrep.2023.112822",

language = "English (US)",

volume = "42",

journal = "Cell reports",

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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

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

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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 -

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

Abstract

Keywords

ASJC Scopus subject areas

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