Loss of ‘Survival of Motor Neurons’ (SMN) leads to spinal muscular atrophy (SMA), a disease characterized by degeneration of spinal cord alpha motor neurons, resulting in muscle weakness, paralysis and death during early childhood. SMN is required for assembly of the core splicing machinery, and splicing defects were documented in SMA. We previously uncovered that Coactivator-Associated Methyltransferase-1 (CARM1) is abnormally up-regulated in SMA, leading to mis-regulation of a number of transcriptional and alternative splicing events. We report here that CARM1 can promote decay of a premature terminating codon (PTC)-containing mRNA reporter, suggesting it can act as a mediator of nonsense-mediated mRNA decay (NMD). Interestingly, this pathway, while originally perceived as solely a surveillance mechanism preventing expression of potentially detrimental proteins, is now emerging as a highly regulated RNA decay pathway also acting on a subset of normal mRNAs. We further show that CARM1 associates with major NMD factor UPF1 and promotes its occupancy on PTC-containing transcripts. Finally, we identify a specific subset of NMD targets that are dependent on CARM1 for degradation and that are also misregulated in SMA, potentially adding exacerbated targeting of PTC-containing mRNAs to the already complex array of molecular defects associated with this disease.

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Although recent advances in gene therapy provide hope for spinal muscular atrophy (SMA) patients, the pathology remains the leading genetic cause of infant mortality. SMA is a monogenic pathology that originates from the loss of theSMN1gene in most cases or mutations in rare cases. Interestingly, severalSMN1mutations occur within the TUDOR methylarginine reader domain of SMN. We hypothesized that inSMN1mutant cases, SMA may emerge from aberrant protein-protein interactions between SMN and key neuronal factors. Using a BioID proteomic approach, we have identified and validated a number of SMN-interacting proteins, including fragile X mental retardation protein (FMRP) family members (FMRFM). Importantly, SMA-linked SMNTUDORmutant forms (SMNST) failed to interact with FMRFM. In agreement with the recent work, we define biochemically that SMN forms droplets in vitro and these droplets are stabilized by RNA, suggesting that SMN could be involved in the formation of membraneless organelles, such as Cajal nuclear bodies. Finally, we found that SMN and FMRP co-fractionate with polysomes, in an RNA-dependent manner, suggesting a potential role in localized translation in motor neurons.

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