Widespread intron retention and exon skipping characterise alternative splicing changes in a C. elegans model of spinal muscular atrophy

Résumé fourni par la source

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced levels of the survival motor neuron (SMN) protein, an essential component of the RNA splicing machinery. Although disruption of alternative splicing is a well-established hallmark of SMA, the specific splicing events that contribute to disease pathogenesis remain poorly understood. We utilised an established Caenorhabditis elegans SMA model to investigate global splicing changes using poly(A)+ RNA-seq and custom transcriptome assembly. Zygotic loss of smn-1 led to extensive transcriptomic changes, including over 1000 alternative splicing events, many of which were functionally tied to larval development. Exon skipping and intron retention were the most prevalent splicing alterations, and sequence motif analysis indicated a general shift from strong to weak splice site usage; however, no single motif accounted for the majority of observed splicing changes. Notably, we identified an overlap between smn-1 dependent splicing and those regulated by U6 snRNA m6A methylation. Our findings reinforce the conserved, broad role of SMN in maintaining splicing fidelity and reveal specific sequence biases associated with splicing errors in SMA.

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