SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.

Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.

Adapting to heatwave-induced seagrass loss: Prioritizing management areas through environmental sensitivity mapping.

Seagrass meadows support complex species assemblages and provide ecosystem services with a multitude of socio-economic benefits. However, they are sensitive to anthropogenic pressures such as coastal development, agricultural run-off, and overfishing. The increasing prevalence of marine heatwaves (MHWs) due to climate change poses an additional and growing threat. In this study, we apply the environmental sensitivity mapping approach MESA (Mapping Environmentally Sensitive Assets) to explore the potential consequences of MHWs on the ecosystem services that Posidonia oceanica provides to coastal communities. Under the intermediate climate change scenario Representative Concentration Pathway 4.5, Mediterranean marine heatwaves will be severe by 2050, and will very likely increase mortality of P. oceanica. However, the societal risk of seagrass loss is not evenly distributed across the Mediterranean. The spatial distribution of socio-economic implications of seagrass loss is highlighted through two case studies on seagrass-dependent fisheries and coastal hazards. Coastal communities in Tunisia and Libya show very high sensitivity to a loss of fisheries due to a combination of increasingly intense and frequent MHWs, coupled with high proportions of regional seagrass-dependent fisheries catch. The coastlines of Italy, Tunisia, and Cyprus are shown to potentially be highly sensitive to loss of seagrass due to high levels of coastal hazards, and seagrass meadows susceptible to MHW-induced degradation. These coastlines are likely to suffer from reduced coastal protection services provided by intact seagrass meadows. We demonstrate the implications of MHWs for ecosystem service provision to coastal communities in the Mediterranean and the need for policy instruments to help mitigate and adapt to its effect. We also highlight the potential for environmental sensitivity mapping to help support policymakers with rapid screening tools to prioritize resources more effectively to areas where in-depth local planning is needed.