Gallotta, I. | Search bioRxiv

bioRxiv2026

A Spinal Muscular Atrophy Model Reveals Both Developmental and Degenerative Neuronal Defects in C. elegans

Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene. SMN1 is ubiquitously expressed and encodes a protein essential for the assembly of small nuclear ribonucleoproteins (snRNPs), key components of pre-mRNA splicing. Beyond this canonical role, SMN participates in several other fundamental cellular processes, including RNA transport, regulation of actin dynamics, transcription, and translation. While multiple hypotheses have been put forward to explain selective motor neuron (MN) vulnerability to SMN deficiency, the precise mechanisms involved remain incompletely understood. In this study, we used a simple and tractable C. elegans model to investigate the molecular mechanisms underlying neuronal degeneration in SMA. Silencing of the smn-1 in targeted neurons resulted in defects in the birth and development of both motor neurons and touch receptor neurons (TRNs). In TRNs SMN-1 depletion caused distinct defects in neuronal process morphology. Our results provide evidence that key aspects of SMA pathology are conserved in C. elegans, which may offer new opportunities to elucidate the molecular mechanisms underlying neuronal degeneration in SMA.

genetics↗

bioRxiv2020

TGS1 controls snRNA 3' end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo

Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5 mono-methylguanosine cap of snRNAs to a trimethylguanosine cap. Here, we show that loss of TGS1 in C. elegans, D. melanogaster and D. rerio results in neurological phenotypes similar to those caused by Survival Motor Neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3 tails that are often uridylated. snRNAs with defective 3 terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.

genetics↗