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    • Introduction Parkinson s Disease PD is

    2022-06-29

    Introduction Parkinson's Disease (PD) is a neurodegenerative disease affecting approximately 5–6 million individuals worldwide [1]. This number is expected to escalate to ∼10 million by the year 2030 as the world's population rapidly ages [2]. In the United States, more than 1 million individuals have PD, and around 60,000 new cases are diagnosed every year, causing a rapidly expanding social, medical, and financial burden. Clinical features of PD include resting tremor, muscle rigidity, bradykinesia, and postural instability, usually appearing when levels of dopamine (DA) in the dorsal striatum display a 70–80% reduction [3], [4], [5], making it very difficult for PD to be detected at early stages. Parkinson's disease etiology is still elusive, and clinical interventions are focused on symptoms management rather than halt of disease progression. Appearing on the clinical scene in the late 60's, l-DOPA administration was the first proposed treatment for PD and is still largely used today, as no major development has occurred regarding effective new treatments [6]. Therefore, a better understanding of how substantia nigra (SN) DA neurons behave and respond to stimuli that may interfere with disease development will likely support the improvement of current clinical approaches. Structurally similar to ghrelin, Dln-101 is a proprietary 24–amino acid, acylated peptide derived from a naturally occurring splice variant of the human ghrelin gene. Julst like ghrelin, Dln101, targets the growth hormone secretagogue 1 receptor (GHSR), present in hypothalamic centers controlling energy metabolism and food intake [7], [8], [9] as well as in the SN [10], a CCG 203971 region where dopamine (DA) cell degeneration leads to PD. Activation of GHSR has been shown to protect SN DA neurons against 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment [11], [12], [13], [14]. The presumable mechanisms underlying GHSR-mediated neuroprotection in rodents include activation of UCP2 and associated decrease in mitochondrial ROS production [12], suppression of the pro-inflammatory cytokines TNFa, IL-6 and IL-1b [15], [16], prevention of MPTP-induced increase in apoptosis-promoting factors caspase-3 and bax, as well as decrease in the anti-apoptotic gene bcl-2 [11], and augmentation of midbrain dopamine neuron electrical activity [17], [18], [19], since there is a growing body of evidence suggesting that the mechanisms that control electrical activity of SN DA neurons are not only crucial for regulating dopamine release in the dorsal striatum [20] but also for the survival of these neurons [21]. Finally, it is well established that mitochondria have a central role in substrate oxidation and energy production with broad consequences for whole cellular physiology [22]. The fission/fusion dynamics of mitochondria are critical not only for controlling mitochondrial shape, size, and number, but also for contributing to the dilution and sequestration of mitochondrial damage, impacting directly its function [23], [24]. Fission, for example, facilitates the distribution of mitochondria in response to local demand for ATP, whereas fusion helps to replace damaged mtDNA and to regenerate damaged/depolarized mitochondria [25], [26]. The fission/fusion dynamics are controlled by opposing actions of different dynamin-family members, dynamin-related protein 1 (Drp1) and mitofusins (Mfns), assisted by mitochondrial outer membrane receptors such as mitochondrial fission 1 (Fis-1) and mitochondrial fission factor (Mff) [27], [28]. Dysfunctional mitochondrial fission/fusion dynamics are believed to be central to the pathophysiology of both familial and sporadic PD [29], [30]. These conclusions are supported by the observation of mitochondrial dysfunction and fragmentation in postmortem studies, including altered expression of proteins related to mitochondrial dynamics [31], [32], identification in PD patients of mutations in genes encoding proteins important for mitochondrial dynamics [33], [34], and increased accumulation of mutations in the mitochondrial DNA of SN DA neurons with age and PD [35], [36].