Skeletal myotubes and muscles expressing human ALS-causing genes | 49704

Journal of Neurology & Neurophysiology

ISSN - 2155-9562

Skeletal myotubes and muscles expressing human ALS-causing genes trigger motoneuron neurodegeneration through the release of a toxic factor(s)

21st World Congress on Neurology and Therapeutics

March 15-17, 2018 | London, UK

Pablo Martinez Contreras, Mari?­a Florencia Tevy, Enrique Jaimovich and Brigitte van Zundert

Universidad Andres Bello, Chile
Universidad Mayor, Chile
Universidad de Chile, Chile

Posters & Accepted Abstracts: J Neurol Neurophysiol

Abstract :

Despite that ALS is considered a central nervous system disease, recent studies show that restricted expression of hSOD1G93A in mouse muscles induces motoneuron degeneration and ALS symptomatology. To gain insights into the mechanisms underlying motoneuron neurodegeneration, we established an in vitro culture model system using rodent hSOD1G93A myotubes and wild-type motoneurons. Muscle conditional media (MCM) was prepared from cultured primary myotubes from neonatal mice expressing human SOD1G93A or C9ORF72 genes. MCM-mSOD1WT and non-transgenic C9ORF72 were used as controls. Wild-type primary rat ventral spinal cord cultures (VSCN) (8-10% motoneurons) at 4 DIV were incubated with MCMs. For each sample we tested motoneuron survival (SMI32/MAP2 immunostaining), ROS production (measured with DCF probe) and c-Abl phosphorylation. MCM-hSOD1G93A and C9ORF72 robustly reduced motoneuron survival (40%) in 7 DIV VSCN cultures. Strong ROS production and c-Abl phosphorylation were observed 30 min after MCM-hSOD1G93A application. Further, we used Drosophila models with muscle-restricted ALS-causing genes to explore whether similar effects could be translated in vivo. Using the fly GAL4/UAS system, we expressed ALS-causing genes (hSOD1G85R, hSOD1A4V, hTDP43 and C9ORF72) under muscle Gal4 promoter MHC. Interestingly, restricted expression of hSOD1G85R, hSOD1A4V, hTDP43 or C9ORF72 in muscles of Drosophila reduced their climbing ability. Altogether our data provide evidence that skeletal muscle cells expressing ALScausing genes lead to motoneuron pathology and neurodegeneration through a non autonomous mechanism. We hypothesize the release of unknown toxic factor (s), as a common neurodegeneration pathway.

Biography :

Pablo Martinez Contreras is a PhD candidate from Universidad Andrés Bello, with part of his thesis work performed at Massachussets Institute of Technology. In recent years, he has contributed to understanding the non-autonomous cellular mechanisms that trigger motor neuron death in ALS in both in vitro and in vivo models. His latest research explores the identification of toxic factors released from skeletal muscle and astrocytes as a possible therapeutic target.