LONDON – Work on a fly model of Parkinson’s disease has helped researchers to obtain a new understanding of some of the genetic abnormalities that cause this condition, which may one day make it possible to provide patients with personalized therapy to relieve the symptoms.

In common with earlier studies, the latest one suggests that at least some cases of Parkinson’s disease are due to specific faults in the mitochondria, the organelles that produce energy for the cell.

“Our study indicates that a particular metabolic pathway in the mitochondria may be affected in some cases of Parkinson’s disease and not in others,” Rüdiger Klein, director of the Max Planck Institute of Neurobiology, told BioWorld Today. “If we can find a way of testing patients with Parkinson’s disease to establish which metabolic pathway is responsible for their symptoms, we may be able to help design a therapy that some patients will respond to.”

Klein and his collaborators reported their findings in a paper in the Jan. 30, 2014, edition of The EMBO Journal, titled “Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants.” The first author is Pontus Klein.

Parkinson’s is the second most common neurodegenerative disease after Alzheimer’s disease, affecting between 1 percent and 2 percent of people over the age of 60. It is caused by loss of the dopamine-manufacturing neurons that originate in the substantia nigra of the brain.

The starting point for the EMBO Journal study was the knowledge that a growth factor called glial cell line-derived neurotrophic factor (GDNF) is highly effective in keeping these dopaminergic neurons alive and healthy. But, surprisingly, clinical trials where GDNF was delivered directly to the brain produced mixed results: some patients responded well but others did not.

UNEVEN RESULTS

Klein and his team decided to probe the mechanism of action of GDNF, to find out if they could understand the reasons for these uneven results. They had at their disposal an established animal model for Parkinson’s disease: genetically modified Drosophila flies.

Although most cases of Parkinson’s disease are sporadic, previous research has identified a few genes that are responsible for the disease in rare inherited cases. One of these is called PINK1; another is called Parkin. When these genes (or rather the fly equivalents) are knocked out in Drosophila, their flight muscles degenerate and some of their dopamine-producing neurons die. The flies cannot fly, and they have defective movements. Studies have shown that these phenotypes result from defects in mitochondrial function.

“We decided to find out whether GDNF signaling in the mutant cells helps to prevent mitochondria from degenerating and instead keep them working,” Klein explained.

The receptor for GDNF on neurons is a molecule called Ret, so the team expressed the gene for Ret in the flight muscles or neurons of Drosophila lacking functional copies of either PINK1 or Parkin. They did not use the gene for the ordinary Ret protein, but instead used a gene encoding an activated form of Ret: this activated form does not need GDNF to be present in order to signal to the interior of the cell.

LINKING GDNF TO MITOCHONDRIAL DEGENERATION

They discovered that when they did this using the PINK1 model, they could rescue the mitochondria from degeneration, both in the flight muscles of the flies and in their neurons.

“This finding links the therapeutic effect of the growth factor GDNF to mitochondrial degeneration in a disease model for Parkinson’s disease,” Klein said. “It was interesting, however, that when we used the Parkin mutant flies, we did not see this rescue of the mitochondria.”

In further experiments, bringing about Ret signaling in a human cell line that lacked PINK1 also prevented the development of abnormal mitochondrial appearance and function.

Additional investigations showed that in PINK1 mutant flies, Ret signaling was able to restore the function of complex I of the electron transport chain in mitochondria – a key player in the ability of mitochondria to continue to produce ATP and therefore energy.

“These results suggest,” Klein concluded, “that patients with Parkinson’s disease are probably a heterogeneous group, and that some of them may have this mitochondrial defect that can be rescued by GDNF and others may not. If we could identify the subgroup that can be treated with GDNF, they may respond to treatment, and this may explain why clinical trials to date have had such mixed results.”