1. Glial cell line-derived neurotrophic factor receptor REarranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo
- Author
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Mart Saarma, Ilari Korhonen, Raimo K. Tuominen, Tanel Visnapuu, Juho-Matti Renko, Eric Ronken, Yulia Sidorova, Merja H. Voutilainen, T. Petteri Piepponen, Arun Kumar Mahato, Maxim M. Bespalov, Mati Karelson, Nita Pulkkinen, Andrii Domanskyi, Jaakko Kopra, Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, Division of Pharmacology and Pharmacotherapy, Regenerative pharmacology group, Regenerative Neuroscience, Centre of Excellence in Stem Cell Metabolism, STEMM - Stem Cells and Metabolism Research Program, Drug Research Program, Timo Petteri Piepponen / Principal Investigator, and Mart Saarma / Principal Investigator
- Subjects
0301 basic medicine ,receptor tyrosine kinase RET agonist ,Dopamine ,Neurturin ,Parkinson's disease ,GENE DELIVERY ,Mice ,DOUBLE-BLIND ,0302 clinical medicine ,PARKINSONS-DISEASE ,Neurotrophic factors ,Glial cell line-derived neurotrophic factor ,Clustered Regularly Interspaced Short Palindromic Repeats ,Research Articles ,NEUROPROTECTION ,glial cell line‐derived neurotrophic factor (GDNF) ,SUBSTANTIA-NIGRA ,biology ,Chemistry ,Neurodegeneration ,INFUSION ,Parkinson Disease ,dopamine neurons ,3. Good health ,Cell biology ,Substantia Nigra ,Neurology ,medicine.drug ,Research Article ,Agonist ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,medicine.drug_class ,Substantia nigra ,Neuroprotection ,03 medical and health sciences ,FACTOR GDNF ,medicine ,Animals ,GFR-ALPHA-1 ,Glial Cell Line-Derived Neurotrophic Factor ,Parkinson Disease, Secondary ,Oxidopamine ,CRISPR associated protein 9 ,Dopaminergic Neurons ,Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 ,glial cell line-derived neurotrophic factor (GDNF) ,3112 Neurosciences ,medicine.disease ,Corpus Striatum ,MODEL ,030104 developmental biology ,nervous system ,biology.protein ,Neurology (clinical) ,NEURTURIN ,030217 neurology & neurosurgery - Abstract
Background Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line–derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro 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‐brain‐barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system. Methods 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‐induced cell death, to activate intracellular signaling pathways both in vitro and in vivo , and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain. Results 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‐type but not from RET‐knockout mice. BT13 protects cultured dopamine neurons from 6‐Hydroxydopamine (6‐OHDA) and 1‐methyl‐4‐phenylpyridinium (MPP+)–induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both in vitro and in vivo, and also stimulates the release of dopamine in the mouse striatum. Conclusion The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease‐modifying treatments against PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.
- Published
- 2020