{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:10:41Z","timestamp":1772169041641,"version":"3.50.1"},"reference-count":232,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2015,5,14]],"date-time":"2015-05-14T00:00:00Z","timestamp":1431561600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal\u2014 mainly because of impaired hepatic urea cycle dysfunction\u2014and increased ammoniagenesis\u2014 mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle\u2014causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia\u2014a neurotoxin\u2014damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER) stress, CDK5 activation, oxidative\/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins\u2019 loss, owing to either ER stress and\/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington\u2019s disease and Parkinsonism.<\/ns4:p>","DOI":"10.12688\/f1000research.6364.1","type":"journal-article","created":{"date-parts":[[2015,5,14]],"date-time":"2015-05-14T11:05:03Z","timestamp":1431601503000},"page":"119","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["A(a)LS: Ammonia-induced amyotrophic lateral sclerosis"],"prefix":"10.12688","volume":"4","author":[{"given":"Bhavin","family":"Parekh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2015,5,14]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"1894-901","DOI":"10.1007\/s00415-014-7424-6","article-title":"Euthanasia and physician-assisted suicide in amyotrophic lateral sclerosis: a prospective study.","volume":"261","author":"M Maessen","year":"2014","journal-title":"J Neurol."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"455-456","DOI":"10.1136\/bmj.280.6212.455","article-title":"Motor neurone disease: a demeaning illness.","volume":"280","author":"R Carus","year":"1980","journal-title":"Br Med J."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"506-515","DOI":"10.2174\/138920211797904043","article-title":"Can transcriptomics cut the gordian knot of amyotrophic lateral sclerosis?","volume":"12","author":"A Henriques","year":"2011","journal-title":"Curr Genomics."},{"key":"ref-4","doi-asserted-by":"crossref","first-page":"166-73","DOI":"10.1097\/01376517-198706000-00009","article-title":"Amyotrophic lateral sclerosis: a challenge for constant adaptation.","volume":"19","author":"N Stone","year":"1987","journal-title":"J Neurosci Nurs."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"e4","DOI":"10.4081\/ni.2011.e4","article-title":"Amyotrophic lateral sclerosis: one or multiple causes?","volume":"3","author":"A Bastos","year":"2011","journal-title":"Neurol Int."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"3470-3479","DOI":"10.1093\/brain\/awq097","article-title":"Lockhart Clarke\u2019s contribution to the description of amyotrophic lateral sclerosis.","volume":"133","author":"M Turner","year":"2010","journal-title":"Brain."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"984-90","DOI":"10.1007\/s12035-013-8578-4","article-title":"Amyotrophic lateral sclerosis and skeletal muscle: an update.","volume":"49","author":"O Pansarasa","year":"2014","journal-title":"Mol Neurobiol."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"661-670","DOI":"10.1038\/nrneurol.2014.184","article-title":"The phenotypic variability of amyotrophic lateral sclerosis.","volume":"10","author":"B Swinnen","year":"2014","journal-title":"Nat Rev Neurol."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"616-30","DOI":"10.1038\/nrneurol.2011.152","article-title":"Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis.","volume":"7","author":"L Ferraiuolo","year":"2011","journal-title":"Nat Rev Neurol."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1750-1326-8-28","article-title":"Genetics of amyotrophic lateral sclerosis: an update.","volume":"8","author":"S Chen","year":"2013","journal-title":"Mol Neurodegener."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"1714-24","DOI":"10.1111\/j.1471-4159.2009.06080.x","article-title":"Transcriptional response of the neuromuscular system to exercise training and potential implications for ALS.","volume":"109","author":"L Ferraiuolo","year":"2009","journal-title":"J Neurochem."},{"key":"ref-12","first-page":"474; author reply 474-5","article-title":"Reversible ALS-like disorder in HIV infection. 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