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.
Highlights
Parkinson disease (PD) is the second most prevalent neurodegenerative disease with two major neuropathological hallmarks: (i) neuronal loss in the substantia nigra leading to striatal dopamine deficiency; and (ii) the intraneuronal inclusion bodies known as Lewy bodies containing α-synuclein (α-syn) aggregates both in central and peripheral nerve systems (Poewe et al, 2017)
MPTP exposure significantly lowered blood sugar which may be directly due to neurotoxic effect and less feeding behavior caused by MPTP, and the reduced blood sugar was improved in the MPTP + GLP-1RA group
Repurposing of drugs has gained the interest of researchers recently and the neuroprotective effect of the type 2 diabetes mellitus (T2DM) drugs GLP-1RA on PD has been demonstrated across a range of experimental models of PD (Athauda and Foltynie, 2016)
Summary
Parkinson disease (PD) is the second most prevalent neurodegenerative disease with two major neuropathological hallmarks: (i) neuronal loss in the substantia nigra leading to striatal dopamine deficiency; and (ii) the intraneuronal inclusion bodies known as Lewy bodies containing α-synuclein (α-syn) aggregates both in central and peripheral nerve systems (Poewe et al, 2017). Nonmotor PD symptoms include constipation and anosmia which may be associated with α-syn aggregation in the gut enteric nerves and the olfactory bulb (Chandra et al, 2017). The linkage between PD and mitochondria can be traced back to the 1980s when the PD research landscape discovered that recreational drug exposure of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused parkinsonism through its mitochondrial toxic byproduct 1-methyl-4-phenylpyridinium (MPP+) (Langston, 2017). Our previous data revealed that targeting mitochondrial complex I provided neuroprotection in cellular and rodent PD models (Lin et al, 2014, 2018). These models are important to predict validity in identifying agents that may be clinically effective (Duty and Jenner, 2011). The primary role of mitochondria in PD pathogenesis was supported genetically as mutations of mitochondria-related genes such as phosphatase and tensin homolog-induced kinase-1 (PINK1), parkin, and DJ-1 were found in members of familial PD (Reynolds et al, 2019)
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