@article {Garcia-Vaquero2022.06.20.496821, author = {Marina Garcia-Vaquero and Marjorie Heim and Barbara Flix and Marcelo Pereira and Lucile Palin and T{\^a}nia M. Marques and Francisco R. Pinto and Javier de Las Rivas and Aaron Voigt and Florence Besse and Margarida Gama-Carvalho}, title = {Analysis of pre-symptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration}, elocation-id = {2022.06.20.496821}, year = {2022}, doi = {10.1101/2022.06.20.496821}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Background Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis share both phenotypic and molecular commonalities, including the fact that they can be caused by mutations in proteins involved in RNA metabolism, namely Smn, TDP-43 and Fus. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the converging motoneuron dysfunction caused by changes in the expression of these ubiquitous genes.Methods In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the orthologues of SMN1, TARDBP and FUS (Smn, TBPH and Caz, respectively). We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown.Results Our integrative approach revealed that although each disease-associated gene regulates a poorly overlapping set of transcripts, they have a concerted effect on a specific subset of protein functional modules, acting through distinct targets. Most strikingly, functional annotation reveals these modules to be involved in critical cellular pathways for neurons and in particular, in neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human genes linked to neuronal disease.Conclusions This work provides a new model explaining how mutations in SMA and ALS-associated disease genes linked to RNA metabolism functionally converge to cause motoneuron dysfunction. The critical functional modules identified represent interesting biomarkers and therapeutic targets given their identification in asymptomatic disease models.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2022/06/20/2022.06.20.496821}, eprint = {https://www.biorxiv.org/content/early/2022/06/20/2022.06.20.496821.full.pdf}, journal = {bioRxiv} }