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{{Amyotrophic lateral sclerosis}}
{{Amyotrophic lateral sclerosis}}


The cause of ALS is not known. An important step toward answering that question came in 1993 when scientists discovered that mutations in the gene that produces the Cu/Zn [[superoxide dismutase]] (SOD1) enzyme were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by [[superoxide]], a toxic free radical. [[Free radicals]] are highly reactive molecules produced by cells during normal [[metabolism]]. Free radicals can accumulate and cause damage to DNA and proteins within cells. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene. Current research, however, indicates that motor neuron death is not likely a result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other way (a gain of function).<ref name="mSOD1 gene deletion does not cause MND">{{cite journal |author=Reaume A, Elliott J, Hoffman E, Kowall N, Ferrante R, Siwek D, Wilcox H, Flood D, Beal M, Brown R, Scott R, Snider W |title=Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury |journal=Nat Genet |volume=13 |issue=1 |pages=43-7 |year=1996 |id=PMID 8673102}}</ref><ref name="wtSOD1 elevatation/elimination do not change disease course">{{cite journal |author=Bruijn L, Houseweart M, Kato S, Anderson K, Anderson S, Ohama E, Reaume A, Scott R, Cleveland D |title=Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1 |journal=Science |volume=281 |issue=5384 |pages=1851-4 |year=1998 |id=PMID 9743498}}</ref>
{{CMG}}{{AE}}{{MMJ}}


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.<ref>{{cite journal |author=Furukawa Y, Fu R, Deng H, Siddique T, O'Halloran T |title=Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice |journal=Proc Natl Acad Sci U S A |volume=103 |issue=18 |pages=7148-53 |year=2006 |id=PMID 16636274}}</ref> 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.<ref>{{cite journal |author=Boillée S, Vande Velde C, Cleveland D |title=ALS: a disease of motor neurons and their nonneuronal neighbors |journal=Neuron |volume=52 |issue=1 |pages=39-59 |year=2006 |id=PMID 17015226}}</ref> 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.
==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.
<ref name="pmid25300936">{{cite journal| author=Al-Chalabi A, Calvo A, Chio A, Colville S, Ellis CM, Hardiman O | display-authors=etal| title=Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. | journal=Lancet Neurol | year= 2014 | volume= 13 | issue= 11 | pages= 1108-1113 | pmid=25300936 | doi=10.1016/S1474-4422(14)70219-4 | pmc=4197338 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25300936  }} </ref>


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 [[blood plasma|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.
==Pathophysiology==
===Pathological 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 also leads to the proliferation of supporting cells- astroglial, microglia, and oligodendrocytes.
<ref name="pmid28700839">{{cite journal| author=Brown RH, Al-Chalabi A| title=Amyotrophic Lateral Sclerosis. | journal=N Engl J Med | year= 2017 | volume= 377 | issue= 2 | pages= 162-172 | pmid=28700839 | doi=10.1056/NEJMra1603471 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28700839  }} </ref>
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.
<ref name="DengChen2011">{{cite journal|last1=Deng|first1=Han-Xiang|last2=Chen|first2=Wenjie|last3=Hong|first3=Seong-Tshool|last4=Boycott|first4=Kym M.|last5=Gorrie|first5=George H.|last6=Siddique|first6=Nailah|last7=Yang|first7=Yi|last8=Fecto|first8=Faisal|last9=Shi|first9=Yong|last10=Zhai|first10=Hong|last11=Jiang|first11=Hujun|last12=Hirano|first12=Makito|last13=Rampersaud|first13=Evadnie|last14=Jansen|first14=Gerard H.|last15=Donkervoort|first15=Sandra|last16=Bigio|first16=Eileen H.|last17=Brooks|first17=Benjamin R.|last18=Ajroud|first18=Kaouther|last19=Sufit|first19=Robert L.|last20=Haines|first20=Jonathan L.|last21=Mugnaini|first21=Enrico|last22=Pericak-Vance|first22=Margaret A.|last23=Siddique|first23=Teepu|title=Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia|journal=Nature|volume=477|issue=7363|year=2011|pages=211–215|issn=0028-0836|doi=10.1038/nature10353}}</ref>


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.
==References==


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.
{{Reflist|2}}


Future research may show that many factors, including a genetic predisposition, are involved in the development of ALS.
==References==
==References==


{{Reflist|2}}
{{Reflist|2}}
 
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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

Pathological 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 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

  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.
  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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