Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
Articolo
Data di Pubblicazione:
2017
Citazione:
Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice / A. Mirra, S. Rossi, S. Scaricamazza, M. Di Salvio, I. Salvatori, C. Valle, P. Rusmini, A. Poletti, G. Cestra, M.T. Carrì, M.O. Cozzolino. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 7:1(2017), pp. 2033.1-2033.14. [10.1038/s41598-017-02195-0]
Abstract:
Several of the 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 suggests 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. In this work, we followed these leads and tested their pathogenic relevance in vivo on motor neuron survival/degeneration. FUS-associated ALS recapitulates, in transgenic mice, crucial molecular features that characterise mouse models of SMA, including defects in snRNPs distribution and alteration in the alternative splicing of genes that have important roles in motor neuron function. Interestingly, decreasing SMN expression in these mice does not modify the disease course nor the molecular phenotypes analysed. Similarly, altering SMN levels by either transgenic overexpression or RNAi-mediated downregulation of SMN does not affect eye degeneration caused by FUS expression in Drosophila. Overall, these findings support the concept that FUS and SMN functionally interact and that FUS acts downstream of SMN-regulated snRNP assembly in the regulation of alternative splicing and gene expression.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
FUS; spinal muscular atrophy; motor neuron diseases; amyotrophic lateral sclerosis; transgenic mice
Elenco autori:
A. Mirra, S. Rossi, S. Scaricamazza, M. Di Salvio, I. Salvatori, C. Valle, P. Rusmini, A. Poletti, G. Cestra, M.T. Carrì, M.O. Cozzolino
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