GDNF receptor agonist supports dopamine neurons in vitro and protects their function in animal model of Parkinson's disease.

Mahato, A. K.; Renko, J.-M.; Kopra, J.; Visnapuu, T.; Korhonen, I.; Pulkkinen, N.; Bespalov, M. M.; Ronken, E.; Piepponen, T. P.; Voutilainen, M. H.; Tuominen, R. K.; Karelson, M.; Sidorova, Y. A.; Saarma, M.

doi:10.1101/540021

bioRxiv · 10.1101/540021

GDNF receptor agonist supports dopamine neurons in vitro and protects their function in animal model of Parkinson's disease.

Mahato, A. K.·Renko, J.-M.·Kopra, J.·Visnapuu, T.·Korhonen, I.·Pulkkinen, N.·Bespalov, M. M.·Ronken, E.·Piepponen, T. P.·Voutilainen, M. H.·Tuominen, R. K.·Karelson, M.·Sidorova, Y. A.·Saarma, M.

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Abstract

Motor symptoms of Parkinsons 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 its clinical use is complicated by pharmacokinetic properties. In the present study we demonstrate the ability of a small molecule agonist of GDNF receptor RET to support the survival of cultured dopamine neurons only when they express GDNF receptors. In addition, BT13 activates intracellular signaling cascades in vivo, stimulates release of dopamine and protect the function of dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) rat model of PD. In contrast to GDNF, BT13 is able to penetrate through the blood-brain-barrier. Thus, BT13 serves as an excellent tool compound for the development of novel disease-modifying treatments against PD.

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Mahato, A. K., Renko, J.-M., Kopra, J., Visnapuu, T., Korhonen, I., Pulkkinen, N., Bespalov, M. M., Ronken, E., Piepponen, T. P., Voutilainen, M. H., Tuominen, R. K., Karelson, M., Sidorova, Y. A., Saarma, M.. 2019-02-04. GDNF receptor agonist supports dopamine neurons in vitro and protects their function in animal model of Parkinson's disease.. https://doi.org/10.1101/540021

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