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To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor wt and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting. Foretinib delayed chemotherapy-induced and Wallerian axonal degeneration in culture by preventing axotomy-induced local energy deficit and preserving mitochondria, and peripheral Wallerian degeneration in vivo. These findings identify a new axon degeneration pathway and a potentially clinically useful therapeutic drug.<\/jats:p>","DOI":"10.1083\/jcb.201705085","type":"journal-article","created":{"date-parts":[[2017,9,6]],"date-time":"2017-09-06T17:26:30Z","timestamp":1504718790000},"page":"3655-3675","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["A neuroprotective agent that inactivates prodegenerative TrkA and preserves mitochondria"],"prefix":"10.1083","volume":"216","author":[{"given":"Konstantin","family":"Feinberg","sequence":"first","affiliation":[{"name":"Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelaida","family":"Kolaj","sequence":"additional","affiliation":[{"name":"Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada 1"},{"name":"Department of Physiology, University of Toronto, Toronto, ON, Canada 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Grinshtein","sequence":"additional","affiliation":[{"name":"Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Krieger","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Moran","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada 2"},{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee L.","family":"Rubin","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freda D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada 1"},{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada 4"},{"name":"Department of Physiology, University of Toronto, Toronto, ON, Canada 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4275-8579","authenticated-orcid":true,"given":"David R.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada 1"},{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada 4"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,9,6]]},"reference":[{"key":"2023072317572793600_bib1","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1111\/j.1365-2990.2012.01308.x","article-title":"Review: Axon pathology in age-related neurodegenerative disorders","volume":"39","author":"Adalbert","year":"2013","journal-title":"Neuropathol. 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