{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:38:07Z","timestamp":1769589487505,"version":"3.49.0"},"reference-count":55,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>This review focuses on the complexities of amyotrophic lateral sclerosis (ALS) onset, highlighting the insidious nature of the disease and the challenges in defining its precise origin and early pathogenic mechanisms. The clinical presentation of ALS is characterised by progressive muscle weakness and wasting, often with widespread fasciculations, reflecting lower motor neuron hyperexcitability. The disease\u2019s pathogenesis involves a prolonged preclinical phase of neuronal proteinopathy, particularly TDP-43 accumulation, which eventually leads to motor neuron death and overt ALS. This review discusses the difficulties in detecting this transition and the implications for early therapeutic intervention. It also addresses the involvement of both the upper and lower motor neuron systems, as well as the importance of following presymptomatic patients with genetic mutations. The significance of understanding the distinct processes of TDP-43 deposition and subsequent neuronal degeneration in developing effective treatments is emphasised.<\/jats:p>","DOI":"10.3390\/brainsci15060601","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T11:55:52Z","timestamp":1748951752000},"page":"601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dynamics of Onset and Progression in Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8717-8914","authenticated-orcid":false,"given":"Michael","family":"Swash","sequence":"first","affiliation":[{"name":"Barts and the London School of Medicine, Queen Mary University of London, London E1 4NS, UK"},{"name":"Department of Neurosciences and Mental Health, Centro Hospitalar Universit\u00e1rio Lisboa Norte, 1649-035 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-0158","authenticated-orcid":false,"given":"Mamede","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Mental Health, Centro Hospitalar Universit\u00e1rio Lisboa Norte, 1649-035 Lisboa, Portugal"},{"name":"Faculdade de Medicina, Instituto de Fisiologia, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"ref_1","unstructured":"Kinnier Wilson, S.A. 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