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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
Published February 10, 2014
Citation Information: J Clin Invest. 2014;124(3):981-999. https://doi.org/10.1172/JCI72723.
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Research Article Neuroscience Article has an altmetric score of 23

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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Figure 6

FUS-R521C mice show increased DNA damage and splicing defects in 5′ noncoding exons in the Bdnf gene.

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FUS-R521C mice show increased DNA damage and splicing defects in 5′ nonc...
(A) Schematic diagrams of the qPCR-based FPG assay to identify oxidized (or “damaged”) nucleotides in genomic DNA. (B) FPG assays reveal DNA damage in the 5′ noncoding exons of the Bdnf gene in cortex and spinal cord in FUS-R521C mice. Statistics use Student’s t test, *P < 0.05; **P < 0.01. (C) A schematic diagram of the mouse Bdnf gene, which includes seven 5′ noncoding exons and exon 8, which contains the entire coding sequence and 3′ UTR. PCR primers to detect the retention of 5′ splice junction are highlighted as black arrows (forward) and blue arrows (reverse). Red bars indicate the synthetic oligoribonucleotides that contain the 5′ splice junctions in noncoding exons. (D) qRT-PCR assays detect the marked retention of 5′ splice junction sequences in the Bdnf mRNA in FUS-R521C brain. (E) Crosslinking immunoprecipitation (CLIP) qRT-PCR assays show that more FUS proteins are bound to the 5′ splice junction sequences in exons 2, 4, and 6 in the Bdnf mRNA in the brain of FUS-R521C mice. Statistics in D and E use Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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