{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T14:18:58Z","timestamp":1772720338852,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,9,8]],"date-time":"2013-09-08T00:00:00Z","timestamp":1378598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"MND Association"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Anatomy"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Amyotrophic lateral sclerosis (<jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>) is a complex neurodegenerative disease with clinical, pathological and genetic overlap with frontotemporal dementia (<jats:styled-content style=\"fixed-case\">FTD<\/jats:styled-content>). No longer viewed as one disease with a single unified cause, <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> is now considered to be a clinicopathological syndrome resulting from a complex convergence of genetic susceptibility, age\u2010related loss of cellular homeostasis, and possible environmental influences. The rapid increase in recent years of the number of genes in which mutations have been associated with <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> has led to <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> models that have generated a wealth of data indicating disruption of specific biochemical pathways and sub\u2010cellular compartments. Data implicating pathways including protein misfolding, <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> splicing, oxidative stress, proteosome and mitochondrial dysfunction in the pathogenesis of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> reinforce a disease model based on selective age\u2010dependent vulnerability of a specific population of cells. To the clinical neurologist, however, <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> presents as a disease of focal onset and contiguous spread. Characteristic regional patterns of involvement and progression suggest that the disease does not proceed randomly but via a restricted number of anatomical pathways. These clinical observations combined with electrophysiological and brain\u2010imaging studies underpin the concept of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> at the macroscopic level as a \u2018system degeneration\u2019. This dichotomy between cellular and systems neurobiology raises the fundamental questions of what initiates the disease process in a specific anatomical site and how the disease is propagated. Is the essence of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content> a cell\u2010to\u2010cell transmission of pathology with, for example, a \u2018prion\u2010like\u2019 mechanism, or does the cellular pathology follow degeneration of specific synaptic networks? Elucidating the interaction between cellular degeneration and system level degeneration will aid modeling of the disease in the earliest phases, improve the development of sensitive markers of disease progression and response to therapy, and expand our understanding of the biological basis of clinical and pathological heterogeneity.<\/jats:p>","DOI":"10.1111\/joa.12107","type":"journal-article","created":{"date-parts":[[2013,9,9]],"date-time":"2013-09-09T03:19:36Z","timestamp":1378696776000},"page":"45-51","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Amyotrophic lateral sclerosis: cell vulnerability or system vulnerability?"],"prefix":"10.1111","volume":"224","author":[{"given":"Kevin","family":"Talbot","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences John Radcliffe Hospital University of Oxford Oxford 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