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

• Published in: Frontiers in molecular neuroscience Vol. 14; p. 697440
• Main Authors: Lin, Tsu-Kung, Lin, Kai-Jung, Lin, Hung-Yu, Lin, Kai-Lieh, Lan, Min-Yu, Wang, Pei-Wen, Wang, Tzu-Jou, Wang, Feng-Sheng, Tsai, Po-Chin, Liou, Chia-Wei, Chuang, Jiin-Haur
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 07.07.2021; Frontiers Media S.A
• Subjects: Adenosine triphosphate; Agonists; Animal models; Animals; Apoptosis; Autophagy; autophagy flux; diabetes mellitus; Diabetes mellitus (non-insulin dependent); Dopamine receptors; Electron transport chain; Enzymes; Etiology; FDA approval; GLP-1; Glucagon; Glucagon-like peptide 1; Kinases; Lewy bodies; Mitochondria; Mitochondrial DNA; mitochondrial morphology; Mitophagy; Molecular Neuroscience; Morphology; Movement disorders; MPTP; NADH-ubiquinone oxidoreductase; Neurodegeneration; Neurodegenerative diseases; Neurons; Neuroprotection; Neurotoxicity; Oxidative stress; Parkinson disease; Parkinson's disease; Pathogenesis; Peptides; Phagocytosis; Phosphorylation; Proteins; Substantia nigra; Synuclein; α-synuclein
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2021.697440

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.