TY - JOUR T1 - <em>FUS</em> ALS-causative mutations impact <em>FUS</em> autoregulation and the processing of RNA-binding proteins through intron retention JF - bioRxiv DO - 10.1101/567735 SP - 567735 AU - Jack Humphrey AU - Nicol Birsa AU - Carmelo Milioto AU - David Robaldo AU - Andrea B Eberle AU - Rahel Kräuchi AU - Matthew Bentham AU - Agnieszka M. Ule AU - Seth Jarvis AU - Cristian Bodo AU - Maria Giovanna Garone AU - Anny Devoy AU - Alessandro Rosa AU - Irene Bozzoni AU - Elizabeth MC Fisher AU - Marc-David Ruepp AU - Oliver Mühlemann AU - Giampietro Schiavo AU - Adrian M Isaacs AU - Vincent Plagnol AU - Pietro Fratta Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/18/567735.abstract N2 - Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease in which the loss of motor neurons induces progressive weakness and death from respiratory failure, typically only 3-5 years after onset. 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 characterised, as most disease models have been based on FUS overexpression, which in itself alters its RNA processing functions. To overcome this, we and others have recently created knock-in models, and have generated high depth RNA-sequencing data on FUS mutants in parallel to FUS knockout. We combined three independent datasets with a joint modelling approach, allowing us to compare the mutation-induced changes to genuine loss of function. We find that FUS ALS-mutations induce a widespread loss of function on expression and splicing, with a preferential effect on RNA binding proteins. Mutant FUS induces intron retention changes through RNA binding, and we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS regulation has been linked to disease, and intriguingly, we find FUS autoregulation to be altered not only by FUS mutations, but also 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. ER -