FUS affects splicing of minor introns: Implications for ALS

Fused in sarcoma (FUS) is a ubiquitously expressed protein of the hnRNP family and has several reported functions in diverse RNA metabolic pathways. Among them regulation of transcription, pre-mRNA splicing, mRNA transport and miRNA processing. In 2009, mutations in the FUS gene were identified to be causative for the motor neuron disease amyotrophic lateral sclerosis (ALS) [1]. ALS is defined by a progressive degeneration of upper and lower motor neurons, leading to fatal paralysis and finally to death [2]. Albeit intensive research, the pathomechanisms by which mutations in the FUS gene cause ALS remain to be elucidated. We discovered that FUS interacts with the U12-type spliceosome constituent U11/12 di-snRNP, binds preferentially to U12-type intron containing mRNA and affects splicing of the U12-type introns. FUS promotes splicing of U-12 type containing mRNAs required for action potential transmission and for functional spinal motor units. Furthermore, an ALS-associated FUS mutant, which forms cytoplasmic aggregates, fails to promote splicing of U12-type introns. Intriguingly, this mutant traps U11 and U12 snRNA in these aggregates, further deteriorating the splicing efficiency of U12-type introns. Collectively, our findings indicate a potential pathomechanism for ALS in which mutations in the FUS gene lead to incorrect splicing of U12-type introns, which are essential for motor neuron function and survival.