Functional interaction of FUS with SMN as a common pathogenic pathway for motor neuron diseases

AIMS: Alterations of RNA metabolism are implicated in FUS-related Amyotrophic Lateral Sclerosis. A physical interaction between FUS and SMN, whose decrease cause Spinal Muscular Atrophy (SMA), has been identified. Given the role of SMN in snRNPs assembly and function, a pathogenic cooperation with FUS in this pathway is reasonable, and might be common to ALS and SMA. Thus, we investigated SMA-linked molecular phenotypes in a FUS-related ALS mouse model. METHODS: We used transgenic (Tg) mice overexpressing wild-type (wt) FUS as ALS model. In these mice we analysed: alterations of snRNAs abundance, snRNPs composition and alternative splicing variants of selected pre-mRNAs, by co-immunoprecipitation of spliceosomal proteins and RT-qPCR analysis of bound snRNAUs , immunofluorescence analysis with antibodies recognizing spliceosomal components and PCR analysis of alternative splicing isoforms . RESULTS: Overexpression of wtFUS is sufficient to cause a severe motor neuron degeneration, that results in early lethality, motor neuron loss and inflammation. Analysis of snRNPs composition revealed that about 60% of motor neurons in Tg mice completely lost these structures, thus suggesting functional alteration of this complex. Indeed, alternative splicing events of selected pre-mRNAs that are affected in SMA models, are also affected in FUS mice. Analysis of snRNAUs levels and their abundance in the spliceosomal complex, however, revealed no significant alterations of their composition. CONCLUSIONS: wtFUS mice, a reliable ALS model, recapitulate important SMA-like features. These evidence suggest that ALS and SMA might share a common pathogenic pathway mediated by alterations in splicing regulation by FUS and SMN.