Amyotrophic lateral sclerosis (ALS) could be considered a neurodegenerative disease that predominantly influences the motor system but with increasingly recognized extra-motor features. Previously the disease was characterized as a type of motor neuron disease (Masrori and Van Damme, 2020). In most patients, the illness progresses relentlessly, with a median lifespan of roughly 3-5 years following symptom start, with respiratory failure accounting for the majority of deaths (Chia et al., 2018). In addition to their motor issues, around half of the patients will experience extra-motor symptoms to some degree (Masrori and Van Damme, 2020). The early symptoms are caused by limb muscle weakness, and complaints are typically bilateral yet asymmetric. The disease involves bulbar muscle and makes eating, chewing, speaking, breathing, and coughing difficult. Upper and lower motor neuron signals are seen on neurologic examination.
It is possible to evaluate several regions that are affected by ALS. Motor neurons in the primary motor cortex and the anterolateral horns of the spinal cord degenerate selectively in ALS (McPhee and Hammer, 2016). In addition, many of the afflicted neurons have cytoskeletal pathology, with intermediate filament accumulations in the cell body and axons (McPhee and Hammer, 2016). There is simply a little glial cell response identified and no signs of inflammation.
The molecular pathogenesis of ALS is the subject of various theories. Glutamate is the most common excitatory neurotransmitter in the CNS, and it generates an excitatory postsynaptic potential and raises the concentration of free intracellular Ca2+ in the postsynaptic neuron’s cytoplasm (McPhee and Hammer, 2016). The eradication of glutamate from the synapse and mechanisms for calcium sequestration and extrusion in the postsynaptic cell soon end this Ca2+ signal, which activates calcium-sensitive enzymes (McPhee and Hammer, 2016). There is a significant reduction in glutamate transport activity in the motor cortex and spinal cord in 60% of individuals with sporadic ALS, but not in other CNS areas (McPhee and Hammer, 2016). This has been connected with a loss of the astrocytic glutamate transporter protein excitation causing transporter of amino acid two (EAAT2), which might be caused by a problem with its messenger RNA splicing. Pharmacologic suppression of glutamate transport causes motor neuron degeneration in cultured spinal cord slices.
Approximately 10% of ALS patients have a family history of the disease, with the other instances being categorized as sporadic. Missense mutations cause 20% of the inherited cases in the cytosolic copper-zinc superoxide dismutase (SOD1) gene on chromosome 21’s long arm (Chia et al., 2018). SOD1 catalyzes the generation of hydrogen peroxide from the superoxide anion. Water is formed after hydrogen peroxide is detoxified by catalase or glutathione peroxidase. Familial ALS is thought to be caused by a gain of function rather than a loss of function of the SOD1 gene product (Chia et al., 2018). The reason is that not all mutations affect SOD1 activity, and the illness is usually transmitted as an autosomal dominant feature.
It is also possible to emphasize the role of TDP-43 in the pathologic changes of ASL. TDP-43, also known as TAR DNA binding protein 43, is a multifunctional RNA/DNA binding protein involved in RNA metabolism (Prasad et al., 2019). In individuals with amyotrophic ALS and degeneration of frontotemporal lobar, hyperphosphorylated and ubiquitinated TDP-43 deposits operate as inclusion bodies in spinal cord and the brain (FTLD) (Prasad et al., 2019). While numerous ALS cases (90–95%) are sporadic (sALS), 5–10% of familial ALS cases are initiated by alterations in the TARDBP gene. The rest (90–95%) are instigated by mutations in other genes: C9ORF72, SOD1, FUS, and NEK1, among others (Prasad et al., 2019). Surprisingly, most sporadic ALS patients (up to 97 percent) have TDP-43 protein deposited in neuronal inclusions (Prasad et al., 2019). This fact indicates that TDP-43 is essential in ALS pathophysiology.
References
Chia, R., Chiò, A., & Traynor, B. J. (2018). Novel genes associated with amyotrophic lateral sclerosis: Diagnostic and clinical implications. The Lancet Neurology, 17(1), 94–102.
Masrori, P., & Van Damme, P. (2020). Amyotrophic lateral sclerosis: A clinical review. European Journal of Neurology, 27(10), 1918–1929.
McPhee, S. J., & Hammer, G. D. (2016). Pathophysiology of disease: An introduction to clinical medicine. McGraw-Hill Education.
Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., & Patel, B. K. (2019). Frontiers iMolecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis.n Molecular Neuroscience, 12.