Figure 1: Proposed mechanisms underlying neurodegeneration in ALS
Many of these pathways are mechanisms of cell death common to a range of neurological disorders, although in the case of amyotrophic lateral sclerosis (ALS), have been derived from studies undertaken predominantly using the SOD1 mouse model. Pathophysiological mechanisms involving more recent genetic discoveries, particularly the C9orf72 hexanucleotide repeat expansion, have yet to be elucidated. Neurodegeneration in ALS might refl ect combinations of glutamate excitoxicity, generation of free radicals, mutant SOD1 enzymes, along with mitochondrial dysfunction and disruption of axonal transport processes through accumulation of neurofi lament intracellular aggregates. Mutations in several ALS-related genes are associated with the formation of intracellular aggregates, which appear harmful to neurons. Activation of microglia results in secretion of proinfl ammatory cytokines resulting in further toxicity. Failure of cytoplasmic mitochondria induces increased susceptibility to glutamate-mediated excitotoxicity, perturbations in motor neuronal energy production, and apoptosis. Mitochondrial dysfunction is associated with increased production of reactive oxygen species (ROS). Cytoplasmic aggregates of SOD1 might directly inhibit conductance of VDAC1, thereby reducing the supply of ADP to mitochondria for ATP generation. Δ ψ =mitochondrial membrane potential.
Kaynak
Controversies and priorities in amyotrophic lateral sclerosis
Lancet Neurol 2013; 12: 310–22
