Chance Observation Offers Surprising Discovery: Are Diseases of the Heart and Brain Connected?
Over the course of nearly two decades as a molecular cardiovascular biologist at Cincinnati Children’s Hospital Medical Center, Jeffrey Robbins, PhD, has developed groundbreaking methods to understand the cellular functions of the heart, providing medical science with new insights into the genetic mysteries of heart disease.
But one insight that came rather unexpectedly ultimately led to his discovery that many of the protein characteristics found in brain diseases such as Alzheimer’s, Parkinson’s and others are similar to those found in heart disease.
Photo Offers Clues
Dr. Robbins has shown that toxic protein clusters (represented by the green areas in the photo above) are abundant in patients with advanced heart disease, as well as in the brains of Alzheimer’s patients.
“I was reading an article on neurodegenerative diseases when I noticed that one of the pictures looked very similar to the ones our lab had of diseased heart models,” explains Dr. Robbins. “This picture made me wonder if these diseases of the brain may be telling us something about heart disease.”
To research this potential connection, Dr. Robbins brought to bear the tools and techniques he and his colleagues have developed through years of research. His laboratory has established ways to direct the heart to synthesize normal and mutant proteins, and can turn these on and off at will. This allows researchers to establish cause-and-effect relationships between the mutant proteins and the development of cardiac disease. By purposely creating the expression of an engineered protein in the heart, scientists can study the consequences of a single genetic manipulation at the molecular, biochemical, cytological and physiologic levels. With this information, scientists can determine whether a protein directly or indirectly causes changes in the heart.
In making the link between neurodegenerative disease and heart disease, Dr. Robbins’ first step was to use the methods developed by his lab to confirm that a mutation in a specific protein was in fact directly linked to cardiomyopathy. At the same time, he was able to determine that this diseased protein formed protein aggregates that interfered with heart function. These particular protein aggregates bore striking similarities to a precursor for beta-amyloids, toxic protein clusters that form in the brains of Alzheimer’s patients.
In Alzheimer’s disease, these precursors or “pre-amyloid oligomers” (PAO) occur when proteins fold incorrectly, leading to the death of brain cells. “There has been a lot of work done on how proteins ‘misfold’ in neurodegeneration,” says Dr.Robbins. “My idea was to test for these same aggregates in heart disease.”
Making the Connection
When Dr. Robbins looked into whether these PAOs were also present in samples taken from pediatric heart failure patients, he was surprised by his findings. “Not only did we find PAOs present in animal models, we found that our samples from heart disease patients were also full of them,” he says. “The surprising thing is, I don’t think anyone really expected to find toxic PAOs inside of heart cells. Now we know that the general pathological processes that can occur during Alzheimer’s disease may also occur in the heart and may be directly linked to heart disease”
Next Step: Treatments
Dr. Robbins says the challenge now is to determine the best way to put these findings to use. “What does the presence of PAOs in heart disease mean?” he asks. “What impact will there be if we can we make these toxic substances go away?” These are the questions he is now attempting to answer.
The primary mission of all of his research, is to determine if manipulating these proteins has the potential to generate therapeutic targets for pediatric and adult heart disease.
