Targeting Parkinson’s Disease Pathways

Mutant Drp1(left) blocks mitochondrial fission, resulting in longer mitochondria (arrow). Fis1 (right) promotes fission, resulting in smaller mitochondria.

Parkinson’s disease develops when brain cells that produce the neurotransmitter dopamine begin to die. Loss of these neurons, and others, leads to involuntary shaking, slowed movements, muscle stiffness, and other problems. Medications can help manage symptoms, but there's no treatment to slow or stop the disease.

The underlying causes of neuron death in Parkinson’s disease aren’t well understood. Recent studies have linked dysfunctional mitochondria as one of the pathways causing neuron death. These organelles convert compounds derived from food into the molecules that cells use for energy. Studies suggest that proteins involved in the dynamics of these organelles—how they divide (fission), combine (fusion), and move—may play a role in Parkinson’s disease.

A team led by Dr. Kim Tieu, who was at the University of Rochester School of Medicine and is now at Plymouth University in the UK, explored the effects of manipulating mitochondrial dynamics in 2 mouse models of the disease. One was a genetic model; another used a neurotoxicant that affects mitochondria. The work was funded by NIH’s National Institute of Environmental Health Sciences (NIEHS), National Institute on Aging (NIA), and others. Results appeared in Nature Communications on November 5, 2014.

The scientists tested the effects of blocking or promoting mitochondrial fission by using genetic engineering techniques. To block fission, they used a mutant version of dynamin-related protein 1 (​Drp1), a protein involved in fission. To promote fission, they boosted levels of Fission-1 (​Fis1), which helps bring Drp1 to mitochondria.

The Drp1 mutant restored dopamine release and protected neurons in both mouse models, while Fis1 did not. To confirm that blocking mitochondrial fission was causing these benefits, the researchers tested a small molecule called Mitochondrial Division Inhibitor-1 (Mdivi-1). Mdivi-1 is a Drp1 inhibitor that’s been shown to block mitochondrial fission. They found that Mdivi-1 also restored dopamine release and protected neurons in the mice.

By the time people are diagnosed with Parkinson’s disease, there’s already substantial neuron damage. Thus, the researchers tested the effects of delaying gene or drug delivery until after nerve damage had occurred. They found that ​mutant Drp1 and ​mdivi-1 both improved dopamine release even after damage to the neuron pathway responsible for dopamine release. The findings suggest that the underlying cellular pathway that causes Parkinson’s disease might be restored even after neuron damage has progressed.

“Our findings show exciting potential for an effective treatment for Parkinson’s disease and pave the way for future in-depth studies in this field,” Tieu says. “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.”

—by Harrison Wein, Ph.D.