Ricerc@Sapienza

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder associated in 20% of the familial cases with mutations in the gene coding for the antioxidant enzyme superoxide dismutase (SOD1). ALS is a multi-systemic and multifactorial disease and recent evidences suggest that skeletal muscle is a primary target in ALS. Indeed muscle specific expression of SOD1 mutant gene in MLC/SOD1G93A transgenic mice reveals muscle atrophy, mitochondrial alterations and neuromuscular junction (NMJ) instability. A critical role in this molecular mechanism is played by Protein Kinase C theta (PKC¿), which is chronically activated in MLC/SOD1G93A mice. PKC¿ pharmacological inhibition restores mitochondrial functionality and neuromuscular damaged phenotype, sustaining the "dying back" hypothesis. Nevertheless whether PKC¿ inhibition can counteract muscle functional decline associated with the disease progression remains unclear, so it might be important to analyze the effects of PKC¿ pharmacological inhibition and/or genetic ablation in SOD1G93A mice.
Metabolic changes associated with muscle espression of SOD1G93A in the MLC/SOD1G93A mice occur independently of motor neuron degeneration, so we'll investigate glucose and lipid metabolism and muscle fiber composition in the mice model of PKC¿ inhibition. It is known that ALS is also related to hypothalamus atrophy, so we'll evaluate markers of hypothalamus atrophy in all mice models above mentioned and metabolites levels involved in melanocortin system. Moreover the superchiasmatic nucleus, that is the central circadian clock, is located in hypothalamus anterior region, so it could be interesting to study circadianicity to evaluate whether the circadian alterations occur independently of motor neuron degeneration and to verify whether NMJ stabilization, due to PKC¿ inhibition, could have effects on hypothalamus defects.