Research Highlight: Studying the Links between Chemical Exposures, Genetics, and Neurodegenerative Disease

Lucio Costa, NND ARE leader
As the US population ages, more and more Americans suffer from neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS).1

Alzheimer’s disease is the 6th leading cause of death in the US. More than 5 million Americans are living with Alzheimer’s.2 In addition, over 500,000 Americans live with Parkinson’s.3

Approximately 5,600 Americans are diagnosed with ALS each year. The life expectancy of an ALS patient averages two to five years from diagnosis, and as many as 30,000 Americans have ALS at any given time. The National Institute of Neurological Disorders and Stroke (NINDS) reports that only 5–10% of ALS cases can be traced to genetics.4

Why and how these neurodegenerative diseases develop is for the most part unknown, and environmental factors such as the potential harmful effects of chemicals may play a role.
Investigators in the CEEH Neurotoxicology and Neurodegenerative Disease (NND) Area of Research Emphasis (ARE) study how certain chemicals can affect growth and development and how this might contribute to neurodegenerative diseases. They also look for genetic variations that might explain why some people are more susceptible to the harmful effects of chemicals than others, and work to understand the actual cellular, biochemical and molecular mechanisms of these neurotoxic chemicals.

Core leader Lucio Costa and Core member Clement Furlong study the gene family Paroxonase (PON), which includes PON1, PON2 and PON3. These genes provide the code that allows the body to produce enzymes to help break down certain kinds of pesticides in the body.

Recently Drs. Costa and Furlong investigated the level of one of these enzymes (confusingly named PON2 after the gene that codes for it) in mouse brain cells after the cells were treated with quercetin, a chemical compound found in fruits and vegetables. Previous research has shown that quercetin is an antioxidant that helps protect cells from the harmful effects of oxidative stress. Under normal conditions, the human body uses oxygen to fuel itself by combining the oxygen we breathe with the food we eat and digest. This process produces dangerous by-products such as “free radicals,” unstable atoms or molecules that wreak havoc in cells. Oxidative stress is a disturbance in the balance of free radicals and anti-oxidant defenses such as quercetin. Oxidative stress is associated with neurodegenerative diseases and also plays a role in age-related degeneration.5

Costa and Furlong’s team treated mouse brain cells (astrocytes) with quercetin. They found that these treated cells had higher levels of the PON2 enzyme, and that the PON2 levels increased in proportion to the concentration of quercetin. The team also measured the concentration of free radicals in the treated cells and found decreased levels of these. These findings suggest that quercetin increased the ability of the cells to destroy harmful free radicals and thus protect them from some of the damage caused by oxidative stress.

In cells taken from control mice that didn’t have the PON2 gene, and therefore didn’t produce the PON2 enzyme, quercetin was significantly less protective against oxidative stress. This suggests that the PON 2 enzyme plays an important role in helping quercetin protect us from free radicals. A next step in this research is to move from cells to animal models and study the effect of quercertin on PON2 levels in complex organisms.

Dr. Costa earned a degree in Pharmacology at the University of Milan and came to the US as a postdoctoral fellow at the University of Texas at Houston. As a post-doc, he was asked to discover why animals could become tolerant to the neurotoxic effects of organophosphorus insecticides. This research project sparked his lifelong interest in the myriad ways that chemicals can harm the nervous system.


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