期刊
JOURNAL OF CELL BIOLOGY
卷 217, 期 11, 页码 3947-3964出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201802151
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类别
资金
- Max Planck Society
- Bruno and Ilse Frick Foundation for ALS Research
- Minna-James-Heineman-Stiftung
- French Muscular Dystrophy Association
- US Muscular Dystrophy Association
- EU Joint Programme-Neurodegenerative Disease Research [ZonMW 733051075, ZonMW 733051073]
- European Research Council [ERC-2017-COG 770244]
- Humboldt Foundation research fellowship
- International Max Planck Research School
- Cell Dynamics and Disease (CEDAD) graduate school
- National Institutes of Health [P40OD018537]
- state North Rhine Westphalia
Cabeza (caz) is the single Drosophila melanogaster orthologue of the human FET proteins FUS, TAF15, and EWSR1, which have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we identified Xrp1, a nuclear chromatin-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly up-regulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knockdown was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1, and the majority of Xrp1-interacting proteins are involved in gene expression regulation. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knockdown substantially rescued the motor deficits and life span of flies expressing ALS mutant FUS in motor neurons, implicating gene expression dysregulation in ALS-FUS pathogenesis.
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