| Autor: |
Mirra A; Fondazione Santa Lucia IRCCS, 00143, Rome, Italy.; Dipartimento di Biologia, Università di Roma 'Tor Vergata', Rome, Italy., Rossi S; Istituto di Farmacologia Traslazionale (IFT), CNR, 00133, Rome, Italy., Scaricamazza S; Fondazione Santa Lucia IRCCS, 00143, Rome, Italy.; Dipartimento di Biologia, Università di Roma 'Tor Vergata', Rome, Italy., Di Salvio M; Istituto di Biologia e Patologia Molecolari (IBPM), CNR, 00185, Rome, Italy.; Dipartimento di Biologia e Biotecnologia 'Charles Darwin', Università di Roma 'Sapienza', 00185, Rome, Italy., Salvatori I; Fondazione Santa Lucia IRCCS, 00143, Rome, Italy., Valle C; Fondazione Santa Lucia IRCCS, 00143, Rome, Italy.; Istituto di Biologia Cellulare e Neurobiologia (IBCN), CNR, 00143, Rome, Italy., Rusmini P; Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133, Milan, Italy., Poletti A; Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133, Milan, Italy., Cestra G; Istituto di Biologia e Patologia Molecolari (IBPM), CNR, 00185, Rome, Italy.; Dipartimento di Biologia e Biotecnologia 'Charles Darwin', Università di Roma 'Sapienza', 00185, Rome, Italy., Carrì MT; Fondazione Santa Lucia IRCCS, 00143, Rome, Italy.; Dipartimento di Biologia, Università di Roma 'Tor Vergata', Rome, Italy., Cozzolino M; Istituto di Farmacologia Traslazionale (IFT), CNR, 00133, Rome, Italy. mauro.cozzolino@ift.cnr.it. |
| Abstrakt: |
Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains 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. regulation of alternative splicing, 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. FUS-associated ALS recapitulates, in transgenic mice, crucial molecular features that characterise mouse models of SMA, including defects in snRNPs distribution and in the alternative splicing of genes important for motor neurons. Notably, altering SMN levels by haploinsufficiency or overexpression does not impact the phenotypes of mouse or Drosophila models of FUS-mediated toxicity. Overall, these findings suggest that FUS and SMN functionally interact and that FUS may act downstream of SMN-regulated snRNP assembly in the regulation of alternative splicing and gene expression. |
