Parkinson's disease (PD) is a neurological disorder caused by the degeneration of dopamine neurons in the brain. Current therapies for this debilitating disease are far from adequate, but a new study suggests that targeting mitochondrial dysfunction in dopamine neurons may be a promising approach to treatment.

Mitochondrial dysfunction has been reported in both familial and sporadic PD. Genetic mutations of proteins that adversely affect mitochondrial function, including PTEN-induced putative kinase-1 (PINK1), have been linked to PD. Mitochondrial dysfunction is also thought to underlie PD induced by synthetic meperidine contaminated with the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

To study the relationship between mitochondrial dysfunction and PD, scientists at the University of Rochester (NY) led by Kim Tieu used two mouse models: one to model genetic PD and one to model environmentally induced PD. In the first model, the gene encoding PINK1 was deleted in the mice. In the second model, mice were administered MPTP. Both groups of mice showed the deficits in striatal dopamine release characteristic of PD, as well as impairments in mitochondrial respiratory function (Nat. Commun. 5, 5244; 2014).

The processes of mitochondrial fission and fusion have an important role in the function of these organelles, because they influence their shape, size, number and location within cells. Mitochondrial fission produces multiple smaller mitochondria, a process that requires the recruitment of the GTPase dynamin-related protein 1 (Drp1) from the cytosol to the outer mitochondrial membrane. In previous studies in PD cell culture models, blocking Drp1 function mitigated mitochondrial dysfunction and neurotoxicity; however, this approach had yet to be tested in animal models.

Using their two PD mouse models, Tieu's team delivered mutated Drp1 to dopamine neurons using an adenovirus in order to inhibit mitochondrial fission in these mice. In the mice lacking PINK1, inhibition of Drp1 attenuated the deficits in mitochondrial respiration and restored pre-existing striatal dopamine release. Similarly, in the mice that had been given MPTP, Drp1 inhibition prevented loss of dopamine neurons.

Said Tieu in a press release, “Our findings show exciting potential for an effective treatment for PD and pave the way for future in-depth studies in this field.” He added, “It's worth noting that other researchers are also targeting this mitochondrial fission/fusion pathway as potential treatments for other neurological diseases such as Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis.”