A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome

Jessica A. Bush; Samantha M. Meyer; Rita Fuerst; Yuquan Tong; Yue Li; Raphael I. Benhamou; Haruo Aikawa; Patrick R.A. Zanon; Quentin M.R. Gibaut; Alicia J. Angelbello; Tania F. Gendron; Yong Jie Zhang; Leonard Petrucelli; Torben Heick Jensen; Jessica L. Childs-Disney; Matthew D. Disney

doi:10.1073/pnas.2210532119

A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G₄C₂)^exp in c9ALS/FTD via the nuclear RNA exosome

Jessica A. Bush, Samantha M. Meyer, Rita Fuerst, Yuquan Tong, Yue Li, Raphael I. Benhamou, Haruo Aikawa, Patrick R.A. Zanon, Quentin M.R. Gibaut, Alicia J. Angelbello, Tania F. Gendron, Yong Jie Zhang, Leonard Petrucelli, Torben Heick Jensen, Jessica L. Childs-Disney, Matthew D. Disney

Institut for Molekylærbiologi og Genetik - RNA-biologi og -innovation

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

11 Citationer (Scopus)

33 Downloads (Pure)

Abstract

A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G4C2)exp, causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G4C2)exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G4C2)exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

Originalsprog	Engelsk
Artikelnummer	e2210532119
Tidsskrift	Proceedings of the National Academy of Sciences (PNAS)
Vol/bind	119
Nummer	48
Antal sider	11
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.2210532119
Status	Udgivet - nov. 2022

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Bush, J. A., Meyer, S. M., Fuerst, R., Tong, Y., Li, Y., Benhamou, R. I., Aikawa, H., Zanon, P. R. A., Gibaut, Q. M. R., Angelbello, A. J., Gendron, T. F., Zhang, Y. J., Petrucelli, L., Heick Jensen, T., Childs-Disney, J. L., & Disney, M. D. (2022). A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G₄C₂)^exp in c9ALS/FTD via the nuclear RNA exosome. Proceedings of the National Academy of Sciences (PNAS), 119(48), Artikel e2210532119. https://doi.org/10.1073/pnas.2210532119

@article{c64b1cee2f4b4d368329562cc33c1c4c,

title = "A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome",

abstract = "A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G4C2)exp, causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G4C2)exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G4C2)exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.",

keywords = "drug design, induced proximity, repeat expansion disorders, RNA, RNA-targeted degradation",

author = "Bush, {Jessica A.} and Meyer, {Samantha M.} and Rita Fuerst and Yuquan Tong and Yue Li and Benhamou, {Raphael I.} and Haruo Aikawa and Zanon, {Patrick R.A.} and Gibaut, {Quentin M.R.} and Angelbello, {Alicia J.} and Gendron, {Tania F.} and Zhang, {Yong Jie} and Leonard Petrucelli and {Heick Jensen}, Torben and Childs-Disney, {Jessica L.} and Disney, {Matthew D.}",

year = "2022",

month = nov,

doi = "10.1073/pnas.2210532119",

language = "English",

volume = "119",

journal = "Proceedings of the National Academy of Sciences (PNAS)",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "48",

}

Bush, JA, Meyer, SM, Fuerst, R, Tong, Y, Li, Y, Benhamou, RI, Aikawa, H, Zanon, PRA, Gibaut, QMR, Angelbello, AJ, Gendron, TF, Zhang, YJ, Petrucelli, L, Heick Jensen, T, Childs-Disney, JL & Disney, MD 2022, 'A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G₄C₂)^exp in c9ALS/FTD via the nuclear RNA exosome', Proceedings of the National Academy of Sciences (PNAS), bind 119, nr. 48, e2210532119. https://doi.org/10.1073/pnas.2210532119

A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G₄C₂)^exp in c9ALS/FTD via the nuclear RNA exosome. / Bush, Jessica A.; Meyer, Samantha M.; Fuerst, Rita et al.
I: Proceedings of the National Academy of Sciences (PNAS), Bind 119, Nr. 48, e2210532119, 11.2022.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome

AU - Bush, Jessica A.

AU - Meyer, Samantha M.

AU - Fuerst, Rita

AU - Tong, Yuquan

AU - Li, Yue

AU - Benhamou, Raphael I.

AU - Aikawa, Haruo

AU - Zanon, Patrick R.A.

AU - Gibaut, Quentin M.R.

AU - Angelbello, Alicia J.

AU - Gendron, Tania F.

AU - Zhang, Yong Jie

AU - Petrucelli, Leonard

AU - Heick Jensen, Torben

AU - Childs-Disney, Jessica L.

AU - Disney, Matthew D.

PY - 2022/11

Y1 - 2022/11

N2 - A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G4C2)exp, causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G4C2)exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G4C2)exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

AB - A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G4C2)exp, causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G4C2)exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G4C2)exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

KW - drug design

KW - induced proximity

KW - repeat expansion disorders

KW - RNA

KW - RNA-targeted degradation

UR - http://www.scopus.com/inward/record.url?scp=85142377076&partnerID=8YFLogxK

U2 - 10.1073/pnas.2210532119

DO - 10.1073/pnas.2210532119

M3 - Journal article

C2 - 36409902

AN - SCOPUS:85142377076

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

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