Pathogenic FUS mutations retain spliceosomal snRNPs in the cytoplasm

Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) are associated with defects in proteins involved in RNA metabolism, but the particular step in RNA metabolism that is vulnerable in motor neurons - if there is one - remains unknown. Here we show that FUS, one of the causative factors in ALS, associates in NSC34 neuronal cells with SMN, the causative factor in SMA. FUS binds to spliceosomal snRNPs downstream of the SMN function, indicating that the two genes work on the same pathway. SnRNP binding of FUS is not affected by pathogenic FUS mutations. Instead, cytoplasmic aggregation of mutated FUS induces a partial mis-localisation of the snRNPs in the cytoplasm, and this is followed by a change in the behaviour of the alternative splicing machinery. The FUS mutations thus have a similar effect as SMN1 deletion in SMA, suggesting that changes in alternative splicing might represent a critical step in motor neuron degeneration.