Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis

Daniel Jutzi; Sébastien Campagne; Ralf Schmidt; Stefan Reber; Jonas Mechtersheimer; Foivos Gypas; Christoph Schweingruber; Martino Colombo; Christine von Schroetter; Fionna E Loughlin; Anny Devoy; Eva Hedlund; Mihaela Zavolan; Frédéric H-T Allain; Marc-David Ruepp

doi:10.1038/s41467-020-20191-3

Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis

Daniel Jutzi, Sébastien Campagne, Ralf Schmidt, Stefan Reber, Jonas Mechtersheimer, Foivos Gypas, Christoph Schweingruber, Martino Colombo, Christine von Schroetter, Fionna E Loughlin, Anny Devoy, Eva Hedlund, Mihaela Zavolan, Frédéric H-T Allain, Marc-David Ruepp

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

Abstract

Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).

Original language	English
Article number	6341
Pages (from-to)	6341
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20191-3
Publication status	Published - 11 Dec 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-020-20191-3

Cite this

Jutzi, D., Campagne, S., Schmidt, R., Reber, S., Mechtersheimer, J., Gypas, F., Schweingruber, C., Colombo, M., von Schroetter, C., Loughlin, F. E., Devoy, A., Hedlund, E., Zavolan, M., Allain, F. H.-T., & Ruepp, M.-D. (2020). Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis. Nature Communications, 11(1), 6341. Article 6341. https://doi.org/10.1038/s41467-020-20191-3

@article{b1925d01eb8b424eacd56d05037b98cf,

title = "Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis",

abstract = "Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).",

author = "Daniel Jutzi and S{\'e}bastien Campagne and Ralf Schmidt and Stefan Reber and Jonas Mechtersheimer and Foivos Gypas and Christoph Schweingruber and Martino Colombo and {von Schroetter}, Christine and Loughlin, {Fionna E} and Anny Devoy and Eva Hedlund and Mihaela Zavolan and Allain, {Fr{\'e}d{\'e}ric H-T} and Marc-David Ruepp",

year = "2020",

month = dec,

day = "11",

doi = "10.1038/s41467-020-20191-3",

language = "English",

volume = "11",

pages = "6341",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Jutzi, D, Campagne, S, Schmidt, R, Reber, S , Mechtersheimer, J, Gypas, F, Schweingruber, C, Colombo, M, von Schroetter, C, Loughlin, FE, Devoy, A, Hedlund, E, Zavolan, M, Allain, FH-T & Ruepp, M-D 2020, 'Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis', Nature Communications, vol. 11, no. 1, 6341, pp. 6341. https://doi.org/10.1038/s41467-020-20191-3

TY - JOUR

T1 - Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis

AU - Jutzi, Daniel

AU - Campagne, Sébastien

AU - Schmidt, Ralf

AU - Reber, Stefan

AU - Mechtersheimer, Jonas

AU - Gypas, Foivos

AU - Schweingruber, Christoph

AU - Colombo, Martino

AU - von Schroetter, Christine

AU - Loughlin, Fionna E

AU - Devoy, Anny

AU - Hedlund, Eva

AU - Zavolan, Mihaela

AU - Allain, Frédéric H-T

AU - Ruepp, Marc-David

PY - 2020/12/11

Y1 - 2020/12/11

N2 - Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).

AB - Mutations in the RNA-binding protein Fused in Sarcoma (FUS) cause early-onset amyotrophic lateral sclerosis (ALS). However, a detailed understanding of central RNA targets of FUS and their implications for disease remain elusive. Here, we use a unique blend of crosslinking and immunoprecipitation (CLIP) and NMR spectroscopy to identify and characterise physiological and pathological RNA targets of FUS. We find that U1 snRNA is the primary RNA target of FUS via its interaction with stem-loop 3 and provide atomic details of this RNA-mediated mode of interaction with the U1 snRNP. Furthermore, we show that ALS-associated FUS aberrantly contacts U1 snRNA at the Sm site with its zinc finger and traps snRNP biogenesis intermediates in human and murine motor neurons. Altogether, we present molecular insights into a FUS toxic gain-of-function involving direct and aberrant RNA-binding and strengthen the link between two motor neuron diseases, ALS and spinal muscular atrophy (SMA).

UR - http://www.scopus.com/inward/record.url?scp=85097503464&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-20191-3

DO - 10.1038/s41467-020-20191-3

M3 - Article

C2 - 33311468

SN - 2041-1723

VL - 11

SP - 6341

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6341

ER -

Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this