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  • Another key component of proper

    2022-05-16

    Another key component of proper DA cell physiology is the basal firing activity of SN DA neurons, which maintains extracellular levels of dopamine in the dorsal striatum that are essential for voluntary movement [106]. Changes in SN DA neuron activity directly impacts the amount of dopamine released in target areas and are largely observed in PD subjects [107] as well as in PD animal models and may occur in the absence of changes in other indirect markers of DA neuron function (e.g. neuron number, DA content) [108], [109]. The proper control of SN DA cell electrical activity is of crucial importance because, on one hand and despite the yet elusive mechanism underlying such effect and identification of all cell types involved [110], augmentation of electrical activity of SN DA neurons is thought to be neuroprotective, as increased survival of DA Zacopride hydrochloride synthesis has been reported with the use of depolarizing agents such as veratridine [19] and K+ [111]. Also in line with these observations, prospective cohort and case–control studies have identified tobacco smoking as the most significant protective factor against the risk of developing PD, decreasing it by 60% in active cigarette smokers in comparison to those who never smoked [112], [113]. The mechanisms involved includes reinforcing cholinergic stimulation of SN DA neurons with nicotine, which also showed to be protective in mouse and monkey MPTP models [114], [115], [116]. Consistently, degeneration of DA neurons has been observed in situations of diminished electrical activity [117], [118], including the use of MPTP, which is linked to the activation of KATP channels and consequently silencing of SN DA neurons [119]. Interestingly, KATP channels-mediated hyperpolarization of SN DA neurons induced by mitochondrial dysfunction was mediated by mitochondrial reactive oxygen species (ROS) [120]. These data suggest that ROS could possibly participate in the demise of SN DA neurons by rendering them electrically inactive [121]. One another hand, SN DA neuron activity and dopamine release relies on a controlled modulation of cytosolic calcium levels [122]. Overactivation of SN DA cells leads to excitotoxicity, causing mitochondrial dysfunction and ultimately neuronal degeneration. Therefore, the fine balance between excitation/inhibition is mandatory for proper SN DA cell function. Based on that, we decided to investigate effects of electrical activity per se on SN DA neuroprotection but also on GHSR-mediated neuroprotection. Our data suggest that, at least for the acute mouse MPTP model, modulation of electrical activity is not associated with neuroprotection and, in fact, is not required for GHSR-mediated ghrelin and Dln101 neuroprotection. Mitochondrial dynamics are tightly coordinated in association with the cell cycle and state, with complex structural and functional interactions leading to fusion and fission of mitochondria to alter the balance of oxidative phosphorylation, rescue damaged mitochondria and regulate reactive oxygen species production. Mitochondrial dynamics are also central to the pathogenesis of idiopathic and toxin-induced cases of PD, as well as several monogenic familial PD forms. Mitochondrial length is the result of competitive balance between GTPase dynamin-like proteins mediators of mitochondrial fusion and fission. Mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane, regulate mitochondrial fusion whereas dynamin-related protein 1 (DRP1) regulates mitochondrial fission; among other supporting proteins involved [27], [28]. Disruption of mitochondrial fission leads to an extensively interconnected and collapsed mitochondrial network, while defects in mitochondrial fusion lead to mitochondrial fragmentation and loss of mitochondrial DNA. As a promoter of mitochondrial fusion, Dln101 is thought to facilitate the exchange of mitochondrial DNA, protein components, and metabolites required for mitochondrial function, conferring increased resilience against MPTP-induced cellular stress. Efficient mitochondrial fusion is important for cell viability, because cells defective in fusion exhibit reduced growth, decreased mitochondrial membrane potential (ΔΨm), and defective respiration, resulting in impaired cellular energy metabolism [123], [124], exactly as observed in patients with PD [125], in both sporadic and genetic forms of the disease [126].