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Cytoplasmic accumulation of phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathological hallmark of most ALS cases. While ALS has traditionally been viewed as a disease confined to the brain, spinal cord and motor nerves, recent studies have reported pTDP-43 pathology in multiple other tissues (skeletal and cardiac muscle, skin, minor salivary glands, gastrointestinal tract and lymph nodes), referred to as\n                    <jats:italic>peripheral pathology.<\/jats:italic>\n                    The detection of pTDP-43 beyond the nervous system suggests that ALS-associated TDP-43 proteinopathy may be more widespread than previously recognized and raises fundamental questions regarding the spatial and temporal landscape of ALS pathology. Peripheral pTDP-43 accumulation may reflect a systemic biological susceptibility affecting multiple tissues, propagation of pathological TDP-43 species between anatomical compartments, or a combination of both mechanisms. While its biological significance is yet to be determined, the presence of pTDP-43 in peripheral tissues broadens the current conceptual framework of ALS. It may also provide new opportunities for pathology-based biomarkers, therapeutic monitoring, and mechanistic studies aimed at understanding disease initiation and progression. However, current evidence is derived from small and methodologically heterogeneous cohorts, and peripheral pTDP-43 pathology is not restricted to ALS, emphasizing the need for larger standardized studies.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03086-3","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:07:54Z","timestamp":1789474074000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy"],"prefix":"10.1007","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1745-8299","authenticated-orcid":false,"given":"Philippe","family":"Codron","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Miranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maelle","family":"Garnier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Gouju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Cassereau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Leblanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Letournel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"3086_CR1","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/nrneurol.2013.203","volume":"9","author":"A Al-Chalabi","year":"2013","unstructured":"Al-Chalabi A, Hardiman O (2013) The epidemiology of ALS: a conspiracy of genes, environment and time. 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The methodological framework was guided by the SANRA recommendations [\n                      \n                      ]. A structured search strategy using predefined keywords was applied to the MEDLINE\/PubMed database until May 1, 2026. References from the studied articles and articles citing them were also considered for selection. Fourteen peer-reviewed original articles directly investigating peripheral or retinal TDP-43 pathology in ALS were identified [\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ,\n                      \n                      ]. The recent preprint by Waldron et al. [\n                      \n                      ] was considered separately because of its direct relevance to emerging molecular detection approaches. Table\n                      \n                      summarizes the seven core histopathological studies based on immunodetection of phosphorylated TDP-43. A total of 69 articles were included in the narrative synthesis. Illustration: Fig.\u00a0\n                      \n                      was created using BioRender.com.","order":4,"name":"Ethics","label":"Methods","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"34"}}