Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons

Federica Rizzo, Monica Nizzardo, Shikha Vashisht, Erika Molteni, Valentina Melzi, Michela Taiana, Sabrina Salani, Pamela Santonicola, Elia Di Schiavi, Monica Bucchia, Andreina Bordoni, Irene Faravelli, Nereo Bresolin, Giacomo Pietro Comi, Uberto Pozzoli, Stefania Corti

Research output: Contribution to journalArticlepeer-review

Abstract

Spinal muscular atrophy is a motor neuron disorder caused by mutations in SMN1. The reasons for the selective vulnerability of motor neurons linked to SMN (encoded by SMN1) reduction remain unclear. Therefore, we performed deep RNA sequencing on human spinal muscular atrophy motor neurons to detect specific altered gene splicing/expression and to identify the presence of a common sequence motif in these genes. Many deregulated genes, such as the neurexin and synaptotagmin families, are implicated in critical motor neuron functions. Motif-enrichment analyses of differentially expressed/spliced genes, including neurexin2 (NRXN2), revealed a common motif, motif 7, which is a target of SYNCRIP. Interestingly, SYNCRIP interacts only with full-length SMN, binding and modulating several motor neuron transcripts, including SMN itself. SYNCRIP overexpression rescued spinal muscular atrophy motor neurons, due to the subsequent increase in SMN and their downstream target NRXN2 through a positive loop mechanism and ameliorated SMN-loss-related pathological phenotypes in Caenorhabditis elegans and mouse models. SMN/SYNCRIP complex through motif 7 may account for selective motor neuron degeneration and represent a potential therapeutic target.

Original languageEnglish
Pages (from-to)276-294
Number of pages19
JournalBrain : a journal of neurology
Volume142
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

ASJC Scopus subject areas

  • Clinical Neurology

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