GDNF/RET signaling in dopamine neurons in vivo
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REVIEW
GDNF/RET signaling in dopamine neurons in vivo James A. Conway 1 & Selvi Ince 1 & Stephanie Black 2 & Edgar R. Kramer 1 Received: 16 June 2020 / Accepted: 24 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The glial cell line–derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal both in tandem and separately to exert many vital functions in the midbrain dopamine system. It is known that Ret has effects on maintenance, physiology, protection and regeneration in the midbrain dopamine system, with the physiological functions of GDNF still somewhat unclear. Notwithstanding, Ret ligands, such as GDNF, are considered as promising candidates for neuroprotection and/or regeneration in Parkinson’s disease, although data from clinical trials are so far inconclusive. In this review, we discuss the current knowledge of GDNF/Ret signaling in the dopamine system in vivo as well as crosstalk with pathology-associated proteins and their signaling in mammals. Keywords Midbrain dopamine system . Cell survival . Protection . Regeneration . Ret . GDNF
Introduction Dopamine (DA) is a neurotransmitter produced by dopamine neurons in the midbrain. DA is involved in a diverse range of functions throughout both the brain and body, including motor control, motivation, reward and emotional regulation (Bjorklund and Dunnett 2007; Leknes and Tracey 2008). The DA system comprises DA neuron cell bodies grouped in the ventral midbrain in the retro-rubral field (RRF), ventral tegmental area (VTA), and substantia nigra (SN) (Fig. 1a,b). Axons from these areas project into the mesostriatal and mesocorticolimbic pathways (Bjorklund and Dunnett 2007). As the name suggests, the mesostriatal pathway connects the SN and a portion of the VTA with the dorsal striatum (Fig. 1b,c). This pathway is particularly important in voluntary movement control. The mesocorticolimbic pathway is involved in emotional, cognitive and reward-based behaviors. It projects from the dorsal SN, VTA and RRF to the ventral striatum (putamen and caudate nucleus), cortex, hippocampus,
* Edgar R. Kramer [email protected] 1
Peninsula Medical School, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth, UK
2
Faculty of Arts, University of Plymouth, Plymouth UK
habenula, septum, olfactory tubercle and nucleus accumbens (NAc). As the midbrain DA system is responsible for such a diverse range of functions, alterations can result in a number of neurological diseases. For example, degeneration of DA neurons in the SN results in a DA deficiency in the dorsal striatum, causing the motor pathology characteristic in Parkinson’s disease (PD) (Fig. 1d) (Goedert et al. 2013; Obeso et al. 2001). As DA neurons are highly heterogeneous, a complex network of signaling pathways and events is involved in the development, maintenance and physiological functioning of the midbrain DA system. In recent years, neurotrophic factors, a multifarious group of polypeptides, have emerg
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