Project: Common RNA-dependent pathways for motor-neuron degeneration in spinocerebellar muscular atrophy and amyotrophic lateral sclerosis

The mechanisms underlying motor neuron diseases like amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remain elusive. Presumably, alterations in RNA/protein complex function and neuronal RNA homeostasis are a common causative event. 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. Since a comprehensive view of the core set of target transcripts and pathways whose misregulation underlies motorneuron degeneration is lacking, we will integrate the complementary expertise of 5 research groups to 1) develop physiological fly models of adult onset SMA and ALS and perform genome-wide analyses of RNA splicing patterns; 2) characterize both normal and pathological RNA and protein composition of the TDP-43/FUS/SMN complexes; 3) identify core gene networks commonly altered in TDP-43, FUS and SMN by a cross-disease computational network analysis; 4) pinpoint functionally relevant networks on the basis of vast genetic screen results available in the consortium; 5) characterize the processing and subcellular distribution of target transcripts in the identified networks, and 6) validate expression in ALS and SMA patient samples. Thus, we will identify the transcriptional and RNA metabolism pathways regulated by TBP-43, FUS and SMN in neuronal cells in vivo as potential critical targets for therapeutic approaches of ALS and SMA.

Acronym Fly-SMALS (Reference Number: JPND_CD_FP-688-085)
Duration 01/01/2015 - 01/01/2018
Project Topic Neurodegenerative disease
Website visit project website
Network JPND
Call A call for European research projects for cross-disease analysis of pathways related to neurodegenerative diseases

Project partner

Number Name Role Country
1 University Hospital RWTH Aachen Coordinator Germany
2 University Hospital RWTH Aachen Partner Germany
3 Université de Nice Partner France
4 University of Lisbon Partner Portugal
5 Centro de Investigación del Cáncer Partner Spain
6 University Hospital RWTH Aachen Partner Germany