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, Eric J. Huang*

*Corresponding author for this work

Research output: Contribution to journalArticle

136 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)981-999
Number of pages19
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
StatePublished - Mar 3 2014

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects'. Together they form a unique fingerprint.

  • Cite this

    Qiu, H., Lee, S., Shang, Y., Wang, W. Y., Au, K. F., Kamiya, S., Barmada, S. J., Finkbeiner, S., Lui, H., Carlton, C. E., Tang, A. A., Oldham, M. C., Wang, H., Shorter, J., Filiano, A. J., Roberson, E. D., Tourtellotte, W. G., Chen, B., Tsai, L. H., & Huang, E. J. (2014). ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. Journal of Clinical Investigation, 124(3), 981-999. https://doi.org/10.1172/JCI72723