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Addendum Free access | 10.1172/JCI149564

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects

Haiyan Qiu, Sebum Lee, Yulei Shang, Wen-Yuan Wang, Kin Fai Au, Sherry Kamiya, Sami J. Barmada, Steven Finkbeiner, Hansen Lui, Caitlin E. Carlton, Amy A. Tang, Michael C. Oldham, Hejia Wang, James Shorter, Anthony J. Filiano, Erik D. Roberson, Warren G. Tourtellotte, Bin Chen, Li-Huei Tsai, and Eric J. Huang

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Published April 1, 2021 - More info

Published in Volume 131, Issue 7 on April 1, 2021
J Clin Invest. 2021;131(7):e149564. https://doi.org/10.1172/JCI149564.
© 2021 American Society for Clinical Investigation
Published April 1, 2021 - Version history
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Related article:

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects
Haiyan Qiu, … , Li-Huei Tsai, Eric J. Huang
Haiyan Qiu, … , Li-Huei Tsai, Eric J. Huang
Research Article Neuroscience

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects

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Abstract

Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf) as a target of FUS-R521C–associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.

Authors

Haiyan Qiu, Sebum Lee, Yulei Shang, Wen-Yuan Wang, Kin Fai Au, Sherry Kamiya, Sami J. Barmada, Steven Finkbeiner, Hansen Lui, Caitlin E. Carlton, Amy A. Tang, Michael C. Oldham, Hejia Wang, James Shorter, Anthony J. Filiano, Erik D. Roberson, Warren G. Tourtellotte, Bin Chen, Li-Huei Tsai, Eric J. Huang

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Original citation: J Clin Invest. 2014;124(3):981–999. https://doi.org/10.1172/JCI72723

Citation for this addendum: J Clin Invest. 2021;131(7):e149564. https://doi.org/10.1172/JCI149564

The RNA-sequencing data for this study have been deposited in the NCBI’s Sequence Read Archive (SRA PRJNA706035).

Footnotes

See the related article at ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects.

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  • Version 1 (April 1, 2021): Electronic publication

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