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FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Humphrey Jack, Birsa Nicol, Milioto Carmelo, McLaughlin Martha, Ule Agnieszka M, Robaldo David, Eberle Andrea B, Kräuchi Rahel, Bentham Matthew, Brown Anna-Leigh, Jarvis Seth, Bodo Cristian, Garone Maria G, Devoy Anny, Soraru Gianni, Rosa Alessandro, Bozzoni Irene, Fisher Elizabeth M C, Mühlemann Oliver, Schiavo Giampietro, Ruepp Marc-David, Isaacs Adrian M, Plagnol Vincent, Fratta Pietro,
Project Towards understanding mechanism and physiological role of nonsense-mediated mRNA decay (NMD)
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Original article (peer-reviewed)

Journal Nucleic Acids Research
Volume (Issue) 48(12)
Page(s) 6889 - 6905
Title of proceedings Nucleic Acids Research
DOI 10.1093/nar/gkaa410

Open Access

Type of Open Access Publisher (Gold Open Access)


AbstractMutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which will alter RNA processing due to FUS autoregulation. We and others have recently created knockin models that overcome the overexpression problem, and have generated high depth RNA-sequencing on FUS mutants in parallel to FUS knockout, allowing us to compare mutation-induced changes to genuine loss of function. We find that FUS-ALS mutations induce a widespread loss of function on expression and splicing. Specifically, we find that mutant FUS directly alters intron retention levels in RNA-binding proteins. Moreover, we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS levels have been linked to disease, and we show here that this novel autoregulation mechanism is altered by FUS mutations. Crucially, we also observe this phenomenon in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.