Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo : Implications for idiopathic Parkinson's disease

Abstract

Mitochondrial dynamics and quality control plays a critical role in the maintenance of mitochondrial homeostasis and function. Pathogenic mutations of many genes associated with familial Parkinson’s disease (PD) caused abnormal mitochondrial dynamics, suggesting a likely involvement of disturbed mitochondrial fission/fusion in the pathogenesis of PD. In this study, we focused on the potential role of mitochondrial fission/fusion in idiopathic PD patients and in neuronal cells and animals exposed to paraquat (PQ), a commonly used herbicide and PD-related neurotoxin, as models for idiopathic PD. Significantly increased expression of dynamin-like protein 1 (DLP1) and a trend towards reduced expression of Mfn1 and Mfn2 were noted in the substantia nigra tissues from idiopathic PD cases. Interestingly, PQ treatment led to a similar changes in the expression of fission/fusion proteins both in vitro and in vivo which was accompanied by extensive mitochondrial fragmentation and mitochondrial dysfunction. Blockage of PQ-induced mitochondrial fragmentation by Mfn2 overexpression protected neurons against PQ-induced mitochondrial dysfunction in vitro. More importantly, PQ-induced oxidative damage and stress signaling as well as selective loss of dopaminergic (DA) neurons in the substantia nigra and axonal terminals in striatum was also inhibited in transgenic mice overexpressing hMfn2. Overall, our study demonstrated that disturbed mitochondrial dynamics mediates PQ-induced mitochondrial dysfunction and neurotoxicity both in vitro and in vivo and is also likely involved in the pathogenesis of idiopathic PD which make them a promising therapeutic target for PD treatment.

MFN2 ameliorates cell apoptosis in a cellular model of Parkinson's disease induced by rotenone

“…For the first time to the best of the authors' knowledge, it was demonstrated that MFN2 ameliorated apoptosis induced by rotenone. This observation was supported by previous reports that MFN2 overexpression attenuated neuronal apoptosis under the conditions of ischemic stroke or neurodegeneration (21)(22)(23), indicating the antiapoptotic effect of MFN2.…”

“…In an in vitro model of ischemic stroke, decreased MFN2 expression was closely associated with increased neuronal apoptosis (21). In addition, reduced MFN2 level was associated with increased oxidative stress and apoptosis of neurons during neurodegeneration (22,23). In the present study, knockdown of MFN2 in a cellular model of PD induced by rotenone aggravated cell apoptosis.…”

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

“…In summary, in the current study, we demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons caused neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-dependent cell-death pathways. Maintaining normal levels of Mfn2 levels and restoration of mitochondrial dynamics may provide protection from neurodegeneration [55].…”

Dynamin‐like protein 1 cleavage by calpain in Alzheimer’s disease

“…Primary cultures of both rat and mouse cortical neurons were prepared from the brains of embryonic pups at day 18 and day 16, respectively, as previously reported (Kaech & Banker, ; Zhao et al, ) with some modification. In brief, the cerebral cortices were dissected from the embryonic brain and dissociated by trypsinization for 10 min at room temperature.…”