Abstract
Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson’s disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP+ induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.
Highlights
Parkinson’s disease (PD) is a progressive neurological disorder that results from the selective loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta region of the midbrain [1]
Our work demonstrates that restoration of mitochondrial dynamics by mitofusin 2 (Mfn2) overexpression protects against neuronal toxicity in an MPTP-based PD
Genetic research on PD has led to the identification of several monogenic forms of the disorder and numerous genetic risk factors increasing the risk of developing PD, only 5–10% of patients suffer from the monogenic form of PD, which can be caused by autosomal-dominant mutations in SNCA, LRRK2, and VPS35 and autosomal-recessive mutations in PINK1, DJ-1, and Parkin [3,4]
Summary
Parkinson’s disease (PD) is a progressive neurological disorder that results from the selective loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta region of the midbrain [1]. Rodents or nonhuman primates exposed to various neurotoxins, especially 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) [6], remain the most widely used Parkinson disease models. MPTP produces reliable lesions of the nigrostriatal dopaminergic pathway and causes dopaminergic neuron loss and motor behavioral deficits after systemic administration in rodents [7,8]. MPTP-based mouse models are used to understand the mechanisms underlying the demise of dopaminergic neurons in PD and to test symptomatic and neuroprotective drugs [8]
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