{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T01:49:44Z","timestamp":1788140984147,"version":"build-2803163510"},"reference-count":73,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T00:00:00Z","timestamp":1760745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MUR","award":["PRIN2022 N. 2022XTM2S3"],"award-info":[{"award-number":["PRIN2022 N. 2022XTM2S3"]}]},{"name":"MUR","award":["PRIN PNRR N. P20225J5NB"],"award-info":[{"award-number":["PRIN PNRR N. P20225J5NB"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Transposable elements (TEs), once regarded as genomic \u201cjunk,\u201d are now recognized as powerful regulators of gene expression, genome stability, and innate immunity. In the context of neurodegeneration, particularly Amyotrophic Lateral Sclerosis (ALS), accumulating evidence implicates TEs as active contributors to disease pathogenesis. ALS is a fatal motor neuron disease with both sporadic and familial forms, linked to genetic, epigenetic, and environmental factors. While coding mutations explain a subset of cases, advances in long-read sequencing and epigenomic profiling have unveiled the profound influence of non-coding regions\u2014especially retrotransposons such as LINE-1, Alu, and SVA\u2014on ALS onset and progression. TEs may act through multiple mechanisms: generating somatic mutations, disrupting chromatin architecture, modulating transcriptional networks, and triggering sterile inflammation via innate immune pathways like cGAS-STING. Their activity is normally repressed by epigenetic regulators, including DNA methylation, histone modifications, and RNA interference pathways; however, these controls are compromised in ALS. Taken together, these insights underscore the translational potential of targeting transposable elements in ALS, both as a source of novel biomarkers for patient stratification and disease monitoring, and as therapeutic targets whose modulation may slow neurodegeneration and inflammation. This review synthesizes the current knowledge of TE biology in ALS; integrates findings across molecular, cellular, and systems levels; and explores the therapeutic potential of targeting TEs as modulators of neurodegeneration.<\/jats:p>","DOI":"10.3390\/ph18101573","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T08:18:54Z","timestamp":1760948334000},"page":"1573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Other Side of the Same Coin: Beyond the Coding Region in Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6246-5901","authenticated-orcid":false,"given":"Paola","family":"Ruffo","sequence":"first","affiliation":[{"name":"Laboratory of Medical Genetics, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"},{"name":"Health Center, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9255-7492","authenticated-orcid":false,"given":"Benedetta","family":"Perrone","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"},{"name":"Health Center, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Perrone","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"},{"name":"Health Center, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7079-1037","authenticated-orcid":false,"given":"Francesca","family":"De Amicis","sequence":"additional","affiliation":[{"name":"Health Center, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Iuliano","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Gr\u00e6cia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-6183","authenticated-orcid":false,"given":"Cecilia","family":"Bucci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5745-9846","authenticated-orcid":false,"given":"Angela","family":"Messina","sequence":"additional","affiliation":[{"name":"Department of Biological, Geological and Environmental Sciences, University of Catania, 95129 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-1783","authenticated-orcid":false,"given":"Francesca Luisa","family":"Conforti","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"},{"name":"Health Center, Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/B978-0-12-802973-2.00013-6","article-title":"The epidemiology of amyotrophic lateral sclerosis","volume":"Volume 138","author":"Talbott","year":"2016","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1111\/ene.14393","article-title":"Amyotrophic lateral sclerosis: A clinical review","volume":"27","author":"Masrori","year":"2020","journal-title":"Eur. 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