Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson’s disease model induced by MPTP

Abstract

Accumulating evidence suggest mitochondria-mediated pathways play an important role in dopaminergic neuronal cell death in Parkinson’s disease (PD). Drp1, a key regulator of mitochondrial fission, has been shown to be activated and translocated to mitochondria under stress, leading to excessive mitochondria fission and dopaminergic neuronal death in vitro. However, whether Drp1 inhibition can lead to long term stable preservation of dopaminergic neurons in PD-related mouse models remains unknown. In this study, using a classical MPTP animal PD model, we showed for the first time Drp1 activation and mitochondrial translocation in vivo after MPTP administration. Inhibition of Drp1 activation by a selective peptide inhibitor P110, blocked MPTP-induced Drp1 mitochondrial translocation and attenuated dopaminergic neuronal loss, dopaminergic nerve terminal damage and behavioral deficits caused by MPTP. MPTP-induced microglial activation and astrogliosis were not affected by P110 treatment. Instead, inhibition of Drp1 mitochondrial translocation diminished MPTP-induced p53, BAX and PUMA mitochondrial translocation. This study demonstrates that inhibition of Drp1 hyperactivation by a Drp1 peptide inhibitor P110 is neuroprotective in a MPTP animal model. Our data also suggest that the protective effects of P110 treatment might be mediated by inhibiting the p53 mediated apoptotic pathways in neurons through inhibition of Drp1-dependent p53 mitochondrial translocation.

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Dominant-negative inhibition of Drp1 in a PINK1 −/− mouse-knockout model of PD, as well as in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice, prevented neuronal death and rescued the impaired dopamine release that is associated with PD (Rappold et al, 2014). More recent work on the MPTP mouse model of PD supports these findings, as p110-TAT-peptidemediated inhibition of Drp1 localization to mitochondria attenuated the death of dopaminergic neurons (Filichia et al, 2016).…”

“…Drp1 has been put forward as a drug target for preventing mitochondrial fragmentation under diverse pathological conditions (Rosdah et al, 2016). Indeed, currently available Drp1 inhibitors have shown neuroprotective properties in animal models of HD (Guo et al, 2013b), PD (Hatch et al, 2014;Filichia et al, 2016) and ischemic stroke (Grohm et al, 2012;Li et al, 2015;Zhang et al, 2013). However, given the widespread expression of the fission enzyme and the detrimental consequences on the development and function of the nervous system upon deletion of Drp1, targeting neuron-specific regulators of Drp1 or other components of the mitochondrial fission/fusion machinery are potentially safer therapeutic strategies.…”

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

“…DLP1 has been proposed forward as a treatment target for preventing mitochondrial fragmentation under various pathological conditions (Guo et al ., 2013; Zhang et al ., 2013; Filichia et al ., 2016; Kim et al ., 2016). The DLP1 mitochondrial fission/fusion machinery as a therapeutic target of prion diseases warrants further study.…”

Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis

“…Lyophilized peptides are stored at −80 °C freezer and are dissolved in sterile water before use. P110 has shown efficacy and no toxicity both in vitro and in animal models in vivo (Filichia et al, 2016; Guo et al, 2013). …”

“…In our previous study we have found that P110 treatment in the dosage of 0.5–3 mg/kg/day range were effective in a Huntington’s disease mouse model (Guo et al, 2013), Parkinson’s disease mouse model (Filichia et al, 2016) and ischemic brain injury in rat (Guo et al, 2014). We tested the dosages of P110 at 0.5 and 1.0 mg/kg/day in our MS mouse model and found that P110 at 1.0 mg/kg/day provided better protection.…”