Amyotrophic lateral sclerosis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
A possible explanation of Amyotrophic lateral Sclerosis pathophysiology must include processes involved in the development of both Familial and Sporadic forms of ALS. The most commonly accepted view suggests that the disorder is the likely result of a complex interplay between genetic and environmental factors. Other theories also suggest that the pathogenesis of ALS is a multistep process. In the Case of Familial ALS pathological genes causing disease are present from birth however accumulation of disease-causing proteins might take time to build up and exposure to environmental toxins might trigger the multistep process. However, in most cases, Amyotrophic lateral Sclerosis is a Sporadic form in which a small impact of genetic factors with a major contribution from environmental factors. Therefore, the most common explanation for ALS pathophysiology is a two-step process of exposure to genetic risk factors and environmental triggers that triggers the downstream cascade pathway. [1]
Pathophysiology
Pathogical Features
The central pathological feature involving Amyotrophic lateral sclerosis is the death of the motor neurons in the motor cortex, the brain stem, and the spinal cord. Pathological neuronal degeneration in the corticospinal tracts leads to thinning and sclerosis of the neuronal tracts. As more neurons die patients with amyotrophic lateral sclerosis experiences symptoms of denervation atrophy of the limbs, and swallowing, speech process becomes difficult with disease progression. The degeneration process of motor neurons is also associated with neuronal inflammation that leads to the proliferation of supporting cells- astroglia, microglia, and oligodendrocytes. [2]
Studies involving transgenic mice have yielded several theories about the role of SOD1 in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily develop ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia) and a shortened lifespan (see article on superoxide dismutase). This indicates that the toxic properties of the mutant SOD1 are a result of a gain in function rather than a loss of normal function. In addition, aggregation of proteins has been found to be a common pathological feature of both familial and sporadic ALS (see article on proteopathy). Interestingly, in mutant SOD1 mice, aggregates (misfolded protein accumulations) of mutant SOD1 were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration.[3] It is speculated that aggregate accumulation of mutant SOD1 plays a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins.[4] Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. However, it is important to remember that SOD1 mutations cause only 10% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. Yet, the ALS-SOD1 mice remain the best model of the disease thus far.
Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die off when they are exposed over long periods to excessive amounts of glutamate (excitotoxicity). Now, scientists are trying to understand what mechanisms lead to a buildup of unneeded glutamate in the spinal fluid and how this imbalance could contribute to the development of ALS. Failure of astrocytes to sequester glutamate from the extracellular fluid surrounding the neurones has been proposed as a possible cause of this glutamate-mediated neurodegeneration. Riluzole is currently the only approved drug for ALS and targets glutamate transporters. Its very modest benefit to patients has bolstered the argument that glutamate is not a primary cause of the disease.
Autoimmune responses which occur when the body's immune system attacks normal cells have been suggested as one possible cause for motor neuron degeneration in ALS. Some scientists theorize that antibodies may directly or indirectly impair the function of motor neurons, interfering with the transmission of signals between the brain and muscles. More recent evidence indicates that the nervous system's immune cells, Microglia, are heavily involved in the later stages of the disease.
In searching for the cause of ALS, researchers have also studied environmental factors such as exposure to toxic or infectious agents. Other research has examined the possible role of dietary deficiency or trauma. However, as of yet, there is insufficient evidence to implicate these factors as causes of ALS.
Future research may show that many factors, including a genetic predisposition, are involved in the development of ALS.
References
- ↑ Al-Chalabi A, Calvo A, Chio A, Colville S, Ellis CM, Hardiman O; et al. (2014). "Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study". Lancet Neurol. 13 (11): 1108–1113. doi:10.1016/S1474-4422(14)70219-4. PMC 4197338. PMID 25300936.
- ↑ Brown RH, Al-Chalabi A (2017). "Amyotrophic Lateral Sclerosis". N Engl J Med. 377 (2): 162–172. doi:10.1056/NEJMra1603471. PMID 28700839.
- ↑ Furukawa Y, Fu R, Deng H, Siddique T, O'Halloran T (2006). "Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice". Proc Natl Acad Sci U S A. 103 (18): 7148–53. PMID 16636274.
- ↑ Boillée S, Vande Velde C, Cleveland D (2006). "ALS: a disease of motor neurons and their nonneuronal neighbors". Neuron. 52 (1): 39–59. PMID 17015226.