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

Several of the recently identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) are deeply associated to RNA metabolism, thus implying dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains so far unknown. Evidence suggest that FUS, that is mutated in familial ALS, and SMN, the causative factor in Spinal Muscular Atrophy (SMA), cooperate to the same molecular pathway, i.e. alternative splicing regulation, and that disturbances in SMN-regulated functions, either caused by depletion of SMN protein (as in the case of SMA) or by pathogenic interactions between FUS and SMN (as in the case of ALS) might be a common theme in both diseases. To provide evidence that SMN functions are altered in a FUS model of ALS, in this project we analysed whether the ALS-like motor neuron pathology that characterizes mice overexpressing human wild-type FUS reproduces key molecular phenotypes that have been identified in SMA mice. Further, we studied potential additive effects of SMN depletion on the disease phenotypes in FUS mice by generating transgenic wild-type FUS mice on an SMN-deficient background. FUS-associated ALS recapitulates, in transgenic mice, crucial molecular features that characterise mouse models of SMA. In particular, analysis of the distribution of snRNPs, a major constituent of the spliceosome, revealed a dramatic reduction of these structures in the motor neurons of FUS mice, thus suggesting functional alteration of this complex. While snRNAUs levels and their abundance in the spliceosomal complex revealed no major alterations, the alternative splicing of selected pre-mRNAs that are affected in SMA models, and that have important roles in motor neuron function, are also affected in FUS mice, further indicating that ALS and SMA are motor neuron diseases linked by a common molecular pathway. Yet, the shortage of SMN expression in these mice does not modify the disease course nor the molecular phenotypes analysed, thus suggesting the existence of a complex interplay between FUS and SMN in the regulation of alternative splicing and gene expression.