Acrolein Promotes The Build-up Of Alpha-synuclein

The molecule acrolein has been identified as appearing to play an important role in the development of Parkinson’s disease, researchers at Purdue University report. The new finding could lead to therapies, potentially including drugs currently on the market, and it could facilitate earlier diagnosis and prevention of the neurological disorder.

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.

What Is Acrolein

Acrolein, is a toxic, foul-smelling byproduct of burning fat (the brain uses fat for fuel) and is normally eliminated from the body. The smell of burnt fat (as when cooking oil is heated to its smoke point) is caused by glycerol in the burning fat breaking down into acrolein.

Connections exist between acrolein gas in the smoke from tobacco cigarettes and the risk of lung cancer. In terms of the “noncarcinogenic health quotient” for components in cigarette smoke, acrolein dominates, contributing 40 times more than the next component, hydrogen cyanide.

The research team has found that the substance can promote the build-up of a protein called alpha-synuclein. When this protein accumulates in a region of the brain called the substantia nigra, it destroys the cell membranes and key machineries of neurons, killing these brain cells.

Dr. Riyi Shi, professor in the Department of Basic Medical Sciences, College of Veterinary Medicine and Weldon School of Biomedical Engineering, sayid 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.”

Co-investigator Jean-Christophe (Chris) Rochet added a cautionary note:

“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 is a professor in the Department of Medicinal Chemistry and Molecular Pharmacology in the College of Pharmacy.

Hydralazine Treatment

Rochet said 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.”

If further studies show that acrolein plays a similar role in Parkinson disease in humans, it may be possible to detect and forestall the disease in its early stages.

Another important finding from the research is that the scientists were able to mitigate and even reverse the effects of Parkinson’s disease in both animal models and cell cultures using hydralazine, a drug used to treat high blood pressure and congestive heart failure.

“Luckily, this is a compound that can bind to the acrolein and remove it from the body,” Dr. Shi said. “It’s a drug already approved for use in humans, so we know there is no toxicity issue.”

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,”

he 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,”

Shi added.

Early Parkinson’s Detection

Shi says that 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,”

he said.

In 2017, Rochet was part of an international team that found, using epidemiological data from Norway, that a common asthma medicine, salbutamol (also known as albuterol) could reduce the risk of Parkinson’s disease by half.

Abeje Ambaw, et al
Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson’s disease
Molecular and Cellular Neuroscience Volume 88, April 2018, Pages 70-82

Image: Jensflorian CC BY-SA 3.0. Immunhistochemical staining of frontal cortex in a DLB case reveals alpha-Synuclein positive inclusions