Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo

Abstract

Mitochondrial dysfunction has been reported in both familial and sporadic Parkinson’s disease (PD). However, effective therapy targeting this pathway is currently inadequate. Recent studies suggest that manipulating the processes of mitochondrial fission and fusion has considerable potential for treating human diseases. To determine the therapeutic impact of targeting these pathways on PD, we used two complementary mouse models of mitochondrial impairments as seen in PD. We show here that blocking mitochondrial fission is neuroprotective in the PTEN-induced putative kinase-1 deletion (PINK1−/−) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. Specifically, we show that inhibition of the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) using gene-based and small molecule approaches attenuates neurotoxicity and restores pre-existing striatal dopamine release deficits in these animal models. These results suggest Drp1 inhibition as a potential treatment for PD.

Proliferation and fission of peroxisomes — An update

“…Recent studies with mdivi-1 (mitochondrial division inhibitor), a small molecule, selective inhibitor of DLP1 [17,86], revealed that inhibition of DLP1 exerts protective effects in heart and cerebral ischemiareperfusion models and provides neuroprotection in Parkinson models [30,129]. Mdivi-1 prevented mitochondrial fission, loss of mitochondrial membrane potential, and cell death in acute brain injury.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…In addition to AD and HD, increased Drp1 activity and mitochondrial fission have also been observed in Parkinson's disease (PD). 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).…”

Development of Treatments and Therapies to Target Mitochondrial Dysfunction

“…More recently inhibition of Drp1 has been tested in two Parkinson's disease models, a PINK1-/-mouse and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model [ 94 ]. This study is important because it was demonstrated that mdivi-1 crosses the blood-brain barrier and in doing so was able to restore a striatal dopamine release defi cit and reduce neurotoxicity.…”