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

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; ... (2020). FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention. Nucleic acids research, 48(12), pp. 6889-6905. Oxford University Press 10.1093/nar/gkaa410

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Mutations 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 wide spread 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry
08 Faculty of Science > Departement of Chemistry and Biochemistry > NCCR RNA & Disease

UniBE Contributor:

Eberle, Andrea Brigitte and Mühlemann, Oliver

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0305-1048

Publisher:

Oxford University Press

Language:

English

Submitter:

Christina Schüpbach

Date Deposited:

28 May 2020 11:07

Last Modified:

12 Jul 2020 02:41

Publisher DOI:

10.1093/nar/gkaa410

BORIS DOI:

10.7892/boris.144156

URI:

https://boris.unibe.ch/id/eprint/144156

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