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

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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

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### Pathological Features

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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 also leads to the proliferation of supporting cells- astroglial, microglia, and oligodendrocytes. [2] The majority of the cases of ALS are sporadic however familial cases account for 5-10% of ALS. Several genes mutations are linked to the pathogenesis of Familial cases of ALS that includes SOD1 (superoxide dismutase), TAR DNA binding protein (TDP-43), and Fused in Sarcoma (FUS) also known as Translocated in Sarcoma (TLS) accounts for almost 30% of cases. Mutations in several other genes can also lead to ALS/ALS-like syndrome. While causes of most of the sporadic ALS and familial ALS are not known yet. However fronto-temporal lobar dementia may occur in some cases of ALS syndrome. Mutations in UBQLN2 encodes for ubiquitin-like proteins ubiquilin-2 which regulates degradation of ubiquitinated proteins. Mutations in UBQLN2 leads to defects in the protein degradation pathway and abnormal protein aggregated which ultimately causes neurodegeneration that accounts for ALS and dementia pathway. [3]

## References

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1. ↑ 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.CS1 maint: Multiple names: authors list (link)
2. ↑ Brown RH, Al-Chalabi A (2017). "Amyotrophic Lateral Sclerosis". N Engl J Med. 377 (2): 162–172. doi:10.1056/NEJMra1603471. PMID 28700839.
3. ↑ Deng, Han-Xiang; Chen, Wenjie; Hong, Seong-Tshool; Boycott, Kym M.; Gorrie, George H.; Siddique, Nailah; Yang, Yi; Fecto, Faisal; Shi, Yong; Zhai, Hong; Jiang, Hujun; Hirano, Makito; Rampersaud, Evadnie; Jansen, Gerard H.; Donkervoort, Sandra; Bigio, Eileen H.; Brooks, Benjamin R.; Ajroud, Kaouther; Sufit, Robert L.; Haines, Jonathan L.; Mugnaini, Enrico; Pericak-Vance, Margaret A.; Siddique, Teepu (2011). "Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia". Nature. 477 (7363): 211–215. doi:10.1038/nature10353. ISSN 0028-0836.

## References

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