Amyotrophic lateral sclerosis (ALS, also called Maladie the Charcot or Lou Gehrig's disease) is a progressive, usually fatal paralytic disorder caused by the degeneration of motor neurons. The cause of ALS is currently unknown, but appears to involve different mechanisms:
1. Oxidative damage. Approximately 20% of all familial cases is linked to mutations in the gene for the cytosolic free radical-scavenging enzyme superoxide dismutase-1 (SOD1). Mutant SOD1 catalyses aberrant biochemical reactions, resulting in the production of potentially damaging reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide and peroxynitrite. The neuronal oxidative damage seen in ALS could be generated by hydroxyl radical (Peroxidase hypothesis) and/or peroxynitrite (Peroxynitrie hypothesis).
2. Glutamate-induced excitotoxicity. Neuronal membrane depolarization after activation of glutamate receptors activates voltage-dependent Ca2+ channels, which allows Ca2+ influx into the cell. Glutamate activity is regulated by receptor inactivation and glutamate reuptake by the transporter protein SLC1A2. It has been shown that this transporter level is reduced in motor cortex and spinal cord of ALS patients. Moreover, oxidative damage by ROS has been suggested as another possible mechanism by which the glutamate transporter SLC1A2 could be inactivated. Thus, this loss of glutamate transporter could lead to an excessive activation of glutamate receptors and a prolonged Ca2+ entry, which could cause excitotoxic degeneration of motor neurons.
3. Neurofilament (NF) inclusion. A pathological hallmark of ALS is the presence of abnormal neurofilament inclusions in the perikaryon and axon of motor neurons. Extensive reduction in NF-L level has been demonstrated in degenerating motor neurons of ALS patients. This protein is required for proper neurofilament assembly and transport, therefore a lack of NF-L can provoke accumulation of NF-M and NF-H, which can lead to perikaryal neurofilament inclusions. Peripherin is another type of intermediate filament protein that has been identified in motor neuron inclusions in ALS patients. Peripherin heterodimerizes with each of the NF subunits to establish an intermediate filament network. However, because of the reduced level of NF-L, the interaction between peripherin and NF-M and NF-H results in disorganized network, triggering the formation of axonal peripherin inclusions.
4. Impaired mitochondrial function. Mitochondrial degeneration, manifested by mitochondrial vacuolization, has been reported in ALS motor neurons. Mutant SOD1, upregulated proteins (Bax), downregulated proteins (Bcl-2, Bcl-xl) present in motor neurons of ALS patients initiate cytochrome c release from the mitochondria into the cytoplasm, which activates caspase-3, leading to motor neuron apoptosis.
ALS pathogenesis involves multiple cascades of events including oxidative damage, excitotoxicity, aberrant protein aggregation, mitochondrial defects, and caspase activation, leading to motor neuron death in ALS patients.