Mitochondrial degeneration during amyotrophic lateral sclerosis

Recent studies suggest that the many, interconnected facets of mitochondrial dysfunction may play a primary role in the pathogenesis of Amyotrophic Lateral Sclerosis. Indeed, mitochondria are one of the primary sites of damage inside motor neurons, whose degeneration underlies onset of paralysis and death in patients, as well as in astrocytes, microglia and muscle, which also play a prominent role in the disease. We have recently obtained evidence that modulation of redox balance and prevention of formation of intra-mitochondria protein aggregates is able to rescue mitochondrial function in models of ALS based on the expression of mutant SOD1s, suggesting that mitochondrial redox-regulated signal transduction pathways may be responsible for the cellular damages observed. To better investigate this issue, we have recently focused our attention on the p66Shc pathway that in cells exerts a central role in the regulation of mitochondrial ROS metabolism, with a possible task in the control of intracellular redox-based signal transduction pathways, and an established role in the control of mitochondrial apoptosis. When p66Shc pathway activation is hampered by functionally-inactive mutants of the protein, mitochondrial phenotypes that are evoked in cultured neuronal cells by overexpression of mutant SOD1s are inhibited, and mitochondrial damage and apoptotic cell death prevented. Most importantly, deletion of p66Shc in the G93A mouse model of the disease ameliorates mitochondrial function, delays onset, improves motor performance and prolongs survival. Our observations thus emphasize the notion that mitochondrial redox signaling plays an important role in this disease.