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      Glucagon-Like Peptide-1 Receptor Agonist Ameliorates 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Neurotoxicity Through Enhancing Mitophagy Flux and Reducing α-Synuclein and Oxidative Stress

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          Abstract

          Parkinson disease (PD) is the second most common neurodegenerative disease without known disease modification therapy to slow down disease progression. This disease has pathological features of Lewy bodies with α-synuclein aggregation being the major component and selective dopaminergic neuronal loss over the substantia nigra. Although the exact etiology is still unknown, mitochondrial dysfunction has been shown to be central in PD pathophysiology. Type 2 diabetes mellitus has recently been connected to PD, and anti-diabetic drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), have been shown to possess neuroprotective effects in PD animal models. The GLP-1RA liraglutide is currently under a phase 2 clinical trial to measure its effect on motor and non-motor symptoms in PD patients. In this study, we used an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to test the possible mechanism of the GLP-1RA liraglutide in the pathogenesis of PD. We show that the neurobehavioral and motor dysfunction caused by the mitochondrial complex I inhibitor, MPTP, can be partially reversed by liraglutide. The GLP-1RA can protect mice from apoptosis of substantia nigra neurons induced by MPTP. MPTP treatment led to imbalanced mitochondrial fusion and fission dynamics, altered mitochondrial morphology, impeded autophagy flux, increased α-synuclein accumulation, and elevated oxidative stress. Specifically, the normalizing of mitochondrial fusion-fission dynamic-related proteins and enhancement of autophagy flux after administration of liraglutide is associated with improving neuronal survival. This suggests that GLP-1RAs may provide potential beneficial effects for PD caused by mitochondrial dysfunction through improvement of mitochondrial morphology balance and enhancing damaged organelle degradation.

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          Most cited references68

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          Parkinson disease

          Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.
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            Mitochondrial membrane potential.

            The mitochondrial membrane potential (ΔΨm) generated by proton pumps (Complexes I, III and IV) is an essential component in the process of energy storage during oxidative phosphorylation. Together with the proton gradient (ΔpH), ΔΨm forms the transmembrane potential of hydrogen ions which is harnessed to make ATP. The levels of ΔΨm and ATP in the cell are kept relatively stable although there are limited fluctuations of both these factors that can occur reflecting normal physiological activity. However, sustained changes in both factors may be deleterious. A long-lasting drop or rise of ΔΨm vs normal levels may induce unwanted loss of cell viability and be a cause of various pathologies. Among other factors, ΔΨm plays a key role in mitochondrial homeostasis through selective elimination of dysfunctional mitochondria. It is also a driving force for transport of ions (other than H+) and proteins which are necessary for healthy mitochondrial functioning. We propose additional potential mechanisms for which ΔΨm is essential for maintenance of cellular health and viability and provide recommendations how to accurately measure ΔΨm in a cell and discuss potential sources of artifacts.
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              Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins

              The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between BCL-2 family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.
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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                07 July 2021
                2021
                : 14
                : 697440
                Affiliations
                [1] 1Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung, Taiwan
                [2] 2Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung, Taiwan
                [3] 3Center of Parkinson’s Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung, Taiwan
                [4] 4Research Assistant Center, Show Chwan Memorial Hospital , Changhua, Taiwan
                [5] 5Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung, Taiwan
                [6] 6Department of Metabolism, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung, Taiwan
                [7] 7Department of Pediatric, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung, Taiwan
                [8] 8Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital , Kaohsiung, Taiwan
                [9] 9Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine , Kaohsiung, Taiwan
                Author notes

                Edited by: Linyi Chen, National Tsing Hua University, Taiwan

                Reviewed by: Young-Ji Shiao, National Research Institute of Chinese Medicine, Taiwan; Wenhai Chou, National Health Research Institutes, Taiwan

                *Correspondence: Chia-Wei Liou, cwliou@ 123456ms22.hinet.net

                This article was submitted to Molecular Signalling and Pathways, a section of the journal Frontiers in Molecular Neuroscience

                Article
                10.3389/fnmol.2021.697440
                8292641
                34305527
                f2b5baae-59d4-4850-b81a-ae4c84d91543
                Copyright © 2021 Lin, Lin, Lin, Lin, Lan, Wang, Wang, Wang, Tsai, Liou and Chuang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 April 2021
                : 14 May 2021
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 68, Pages: 17, Words: 0
                Funding
                Funded by: Ministry of Science and Technology 10.13039/501100003711
                Award ID: MOST 109-2314-B-182A-076-MY3
                Award ID: 106-2314-B-182A-057-MY3
                Funded by: Chang Gung Memorial Hospital 10.13039/100012553
                Award ID: CGMRP8H0193
                Award ID: CGMRP8I0232
                Categories
                Molecular Neuroscience
                Original Research

                Neurosciences
                glp-1,autophagy flux,parkinson disease,mitochondrial morphology,α-synuclein,diabetes mellitus,mitochondrial dynamics,mega-mitochondria

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