Scientists identified key factor in development of Parkinson’s disease

It could facilitate earlier diagnosis and prevention of the neurological disorder.

Purdue University researchers Jean-Christophe “Chris” Rochet and Dr. Riyi Shi say their discovery of a key factor in the development of Parkinson’s disease could lead to new therapies, potentially including drugs currently on the market; it could facilitate earlier diagnosis and prevention of the neurological disorder. (Purdue University photo/Alex Kumar)
Purdue University researchers Jean-Christophe “Chris” Rochet and Dr. Riyi Shi say their discovery of a key factor in the development of Parkinson’s disease could lead to new therapies, potentially including drugs currently on the market; it could facilitate earlier diagnosis and prevention of the neurological disorder. (Purdue University photo/Alex Kumar)

Parkinson’s disease is a chronic, irreversible disease, and it is the leading cause of disability in people over the age of 60 — affecting nearly one million people in the United States and 7-10 million worldwide. It is the 14th leading cause of death in the United States and the second leading neurological cause of death, behind Alzheimer’s disease. The disease can occur either early or late in life, and its symptoms — tremors, slow movements, difficulty walking — get progressively worse over time.

The risk of developing the disease is thought to be determined by both genetic and environmental factors.

Now, scientists at the Purdue University have identified a compound that accumulates in Parkinson’s disease-affected brain tissue. The compound called acrolein plays a key role in the development of Parkinson’s disease. It is a toxic, foul-smelling byproduct of burning fat and normally eliminated from the body.

These images of a brain cell culture show dopamine neurons similar to those that die in the brains of Parkinson’s disease patients. The image on the left shows a cell culture stained to reveal a marker present in all neurons (red) or only in dopamine neurons (green). The right panel shows a merged image in which a dopamine neuron is stained yellow. (Purdue University image/Aswathy Chandran)
These images of a brain cell culture show dopamine neurons similar to those that die in the brains of Parkinson’s disease patients. The image on the left shows a cell culture stained to reveal a marker present in all neurons (red) or only in dopamine neurons (green). The right panel shows a merged image in which a dopamine neuron is stained yellow. (Purdue University image/Aswathy Chandran)

The compound is known for promoting the growth of a protein called alpha-synuclein. Once the protein accumulates in the brain region, substantia nigra, it destroys the cell membranes and key mechanisms of neurons.

Dr. Riyi Shi, professor in the Department of Basic Medical Sciences, College of Veterinary Medicine and Weldon School of Biomedical Engineering, says that when this cell death becomes extensive enough, the symptoms of Parkinson’s disease becomes evident.

“Acrolein is a novel therapeutic target, so this is the first time it’s been shown in an animal model that if you lower the acrolein level you can actually slow the progression of the disease. This is very exciting. We’ve been working on this for more than 10 years.”

Jean-Christophe (Chris) Rochet, professor in the Department of Medicinal Chemistry and Molecular Pharmacology in the College of Pharmacy, and a co-investigator on the study adds a cautionary note (this is the bad news).

“In decades of research, we’ve found many ways to cure Parkinson’s disease in pre-clinical animal studies, and yet we still don’t have a disease therapy that stops the underlying neurodegeneration in human patients. But this discovery gets us further down the drug-discovery pipeline, and it’s possible that a drug therapy could be developed based on this information.”

Rochet says that in experiments using both animal models and cell cultures, the role of acrolein was confirmed.

“We’ve shown that acrolein isn’t just serving as a bystander in Parkinson’s disease. It’s playing a direct role in the death of neurons.”

From this discovery, scientists were able to mitigate and even reverse the effects of Parkinson’s disease in both animal models and cell cultures. They used a drug called hydralazine, that usually used to treat high blood pressure and heart failure.

Moreover, the drug can bind to the acrolein and remove it from the body.

Rochet cautions that the drug may not ultimately be the best therapy for Parkinson’s. “Because it is used to lower blood pressure, it might not be the best choice for Parkinson’s patients. Or, we may find there is a therapeutic window, a lower dose, that could work without leading to unwanted side-effects. Regardless, this drug serves as a proof of principle for us to find other drugs that work as a scavenger for acrolein.”

Shi said, “It is for this very reason. we are actively searching for additional drugs that can either more efficiently lower acrolein, or do so with fewer side-effects. Actually, we have already identified multiple candidates that can lower acrolein with similar or greater effectiveness, but without lowering blood pressure, providing further hope that such a strategy could be successful in Parkinson’s patients.”

“Early detection of Parkinson’s disease is critical — symptoms often aren’t noticeable until approximately 50 percent of the neural cells in the substantia nigra have died.”

“The key is to have a biomarker for acrolein accumulation that can be detected easily, such as using urine or blood. Fortunately, we have already established such a test using urine or blood samples.”

“The goal is that in the near future we can detect this toxin years before the onset of symptoms and initiate therapy to push back the disease. We might be able to delay the onset of this disease indefinitely. That’s our theory and goal.”

This work was supported by the Indiana State Department of Health grant number 204200 and by funding from the National Institutes of Health, grant numbers NS073636 and NS049221. This research also was funded in part by the Stark Neurosciences Research Institute, Eli Lilly and Co., the Indiana Clinical and Translational Sciences Institute, and the Branfman Family Foundation.

The research is published in the April issue of the scientific journal Molecular and Cellular Neuroscience.