Common RNA-dependent pathways for motor-neuron degeneration in spinocerebellar muscular atrophy and amyotrophic lateral sclerosis – Fly-smals

The pathogenic mechanisms underlying motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remain elusive. Strikingly, recent lines of evidence have suggested that alterations in RNA/protein complex function and neuronal RNA homeostasis may represent a common causative event triggering motor neuron pathology in both ALS and SMA. Indeed, mutations in the three conserved RNA associated proteins TDP-43, FUS and SMN cause ALS and SMA respectively, and induce formation of non-functional ribonucleoprotein complexes. To date, however, a comprehensive understanding of the core set of target transcripts and pathways whose dysregulation underlies motor neuron degeneration is lacking.
Here, we propose to unite the complementing expertise of five research groups to develop an integrative systems approach toward comparative analysis of common gene networks and RNA metabolism pathways underlying both SMA and ALS. Our consortium will combine the power of Drosophila genetics and disease models with RNA/protein complex purifications and integrative transcriptomics and ribonomics computational analyses. Clinical relevance of the identified networks will be validated in ALS and SMA patient samples.
Specifically, we will develop fly models of adult onset SMA and ALS, and perform genome-wide analyses of RNA splicing patterns and abundance in these conditions. In parallel, we will characterize the RNA and protein composition of the TDP-43/FUS/SMN complexes in neuronal cells in vivo. To identify core gene networks commonly altered in TDP-43, FUS and SMN models, we will perform a cross-disease computational network analysis of the obtained data sets. To focus on functionally relevant networks, we will rely on genetic screen results available in the consortium and perform complementary functional studies. Finally, we will characterize the precise processing and subcellular distribution of target transcripts belonging to the identified functional common networks, and confirm their expression in clinical samples from ALS and SMA patients.
With this program, we will identify the transcriptional and post-transcriptional networks regulated by TBP-43, FUS and SMN in neuronal cells in vivo, to prove our hypothesis of common and conserved pathways in both diseases that may represent critical targets for therapeutic approaches.