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This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons but also the surrounding glial cells, and the target skeletal muscle fibers. Here, we analyze the multiple roles of TGFB in these cell types, and how TGFB signaling is altered in ALS tissues. Data reported support a crucial involvement of TGFB in the etiology and progression of ALS, leading us to hypothesize that an imbalance of TGFB signaling, diminished at the pre-symptomatic stage and then increased with time, could be linked to ALS progression. A reduced stimulation of the TGFB pathway at the beginning of disease blocks its neuroprotective effects and promotes glutamate excitotoxicity. At later disease stages, the persistent activation of the TGFB pathway promotes an excessive microglial activation and strengthens muscular dysfunction. The therapeutic potential of TGFB is discussed, in order to foster new approaches to treat ALS.<\/jats:p>","DOI":"10.3390\/ijms21124291","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T13:20:43Z","timestamp":1592313643000},"page":"4291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3250-5591","authenticated-orcid":false,"given":"Mariarita","family":"Galbiati","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Crippa","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9989-0733","authenticated-orcid":false,"given":"Paola","family":"Rusmini","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2719-846X","authenticated-orcid":false,"given":"Riccardo","family":"Cristofani","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elio","family":"Messi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Piccolella","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Tedesco","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Casarotto","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Chierichetti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8883-0468","authenticated-orcid":false,"given":"Angelo","family":"Poletti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,16]]},"reference":[{"key":"ref_1","first-page":"57","article-title":"Variation in worldwide incidence of amyotrophic lateral sclerosis: A meta-analysis","volume":"46","author":"Marin","year":"2017","journal-title":"Int. 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