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Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line\u2013derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons <jats:italic>in vitro<\/jats:italic> and in animal models of PD, but the clinical use of GDNF is complicated by its pharmacokinetic properties. The present study aimed to evaluate the neuronal effects of a blood\u2010brain\u2010barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We characterized the ability of BT13 to activate RET in immortalized cells, to support the survival of cultured dopamine neurons, to protect cultured dopamine neurons against neurotoxin\u2010induced cell death, to activate intracellular signaling pathways both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic><jats:italic>,<\/jats:italic> and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>BT13 potently activates RET and downstream signaling cascades such as Extracellular Signal Regulated Kinase and AKT in immortalized cells. It supports the survival of cultured dopamine neurons from wild\u2010type but not from RET\u2010knockout mice. BT13 protects cultured dopamine neurons from 6\u2010Hydroxydopamine (6\u2010OHDA) and 1\u2010methyl\u20104\u2010phenylpyridinium (MPP<jats:sup>+<\/jats:sup>)\u2013induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, and also stimulates the release of dopamine in the mouse striatum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease\u2010modifying treatments against PD. \u00a9 2019 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.27943","type":"journal-article","created":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T07:33:41Z","timestamp":1576481621000},"page":"245-255","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Glial Cell Line\u2013Derived Neurotrophic Factor Receptor Rearranged During Transfection Agonist Supports Dopamine Neurons <i>In Vitro<\/i> and Enhances Dopamine Release <i>In Vivo<\/i>"],"prefix":"10.1002","volume":"35","author":[{"given":"Arun Kumar","family":"Mahato","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Institute of Biotechnology, Helsinki Institute of Life Science, Viikinkaari 5D University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaakko","family":"Kopra","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juho\u2010Matti","family":"Renko","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanel","family":"Visnapuu","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilari","family":"Korhonen","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nita","family":"Pulkkinen","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim M.","family":"Bespalov","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Institute of Biotechnology, Helsinki Institute of Life Science, Viikinkaari 5D University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrii","family":"Domanskyi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Institute of Biotechnology, Helsinki Institute of Life Science, Viikinkaari 5D University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Ronken","sequence":"additional","affiliation":[{"name":"Solvay Pharmaceuticals  Weesp Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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