Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Common Pathogenic Pathways and Therapeutics for SMA and ALS motoneuron diseases

Project Coordinator

INM, Inserm UMR105


Rashmi Kothary Ottawa Hospital Research Institute Ottawa, Canada
Patrick Aebischer Swiss Federal Institute of Technology, Brain Mind Institute Lausanne, Switzerland

Spinal muscular atrophy (SMA) is an incurable paralytic neuromuscular disorder that mainly affects children at an incidence of 1 in 6000 to 10000 births. SMA is characterized by the selective degeneration of spinal motoneurons. About 95% of SMA cases are caused by autosomal loss-of-function mutations in the SMN1 gene. Recent work has shown that SMA and amyotrophic lateral sclerosis (ALS), another devastating motoneuron pathology, share converging aberrant pathways. The motoneuron-restricted death pathway triggered by Fas and its ligand FasL, contributes to the loss of motoneurons in ALS. Our preliminary data shows that Fas is markedly upregulated in spinal cord motoneurons of SMA mice, suggesting that Fas may also contribute to SMA pathogenesis. Additional preliminary data demonstrates that whereas Fas undeniably induces motoneuron death, it also promotes neuronal outgrowth. Therefore, the same factor may be implicated in compensatory axonal plasticity as well as in the selective loss of neurons. Here, we propose to further dissect the functional duality of Fas and investigate the contribution of the Fas pathway in SMA pathogenesis. Activation and expression profile of the Fas pathway will be assessed in Smn depleted motoneurons, in a SMA mouse model and in human SMA spinal cord. Further, gene therapy approaches will be developed to reduce Fas activity in the spinal cord and specifically target FasL to axons in SMA mice. The ultimate goal of this collaborative endeavor is to generate common therapeutic strategies for SMA and ALS, as well as for other motoneuron diseases.

E-Rare 2012 - Created by Toussaint Biger