{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T03:07:25Z","timestamp":1773976045118,"version":"3.50.1"},"reference-count":348,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Servier (2014) and Fight MND"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>As so many drugs have failed in ALS a new approach is needed. The author proposes that recent human genetic variants may play major roles in the disease, changing metabolism. Evolution of hominins was accelerated 3\u20132.5 Mya, by cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) becoming a unitary pseudogene after a pathogenic infection, changing the sialome, and hence metabolism, brain development and neuromuscular junctions (NMJs). This was when hominins evolved to run in Africa and develop bigger brains. Deletion of CMAH in mice allows them to run for longer (~50%). The enzyme CMAH is critical for the sialome, particularly the neurotrophin GM1, a critical hub for viral infection and for NMJ stability, but which is lost from NMJs at the beginning of denervation, probably due a 10-fold increase in spinal cord glucosylceramidases (non-lysosomal GBA2). A GBA2 inhibitor, ambroxol, is currently in phase II for ALS. Human-specific GM1 may be critical for human evolution, lactate metabolism and ALS. Lipid\/lactate metabolism changed to support these evolutionary changes and lactate is a major body\/brain fuel, but compromised in ALS patients and a marker of disease progression. Recent progress in sports science involving lactate metabolism and human performance may also be relevant to ALS therapies, and incidence.<\/jats:p>","DOI":"10.3390\/cells14211734","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T07:58:05Z","timestamp":1762329485000},"page":"1734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Does Amyotrophic Lateral Sclerosis (ALS) Have Metabolic Causes from Human Evolution?"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1248-8221","authenticated-orcid":false,"given":"Michael","family":"Spedding","sequence":"first","affiliation":[{"name":"Spedding Research Solutions SAS, 78110 Le Vesinet, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e613","DOI":"10.1212\/WNL.0000000000207474","article-title":"Global Prevalence and Incidence of Amyotrophic Lateral Sclerosis: A Systematic Review","volume":"101","author":"Wolfson","year":"2023","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/cjp2.297","article-title":"pTDP-43 aggregates accumulate in non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis: A case series linking archival surgical biopsies with clinical phenotypic data","volume":"9","author":"Pattle","year":"2023","journal-title":"J. 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