Aging Well
Brain Health

Molecular Chaperones, Aging, and Neurodegenerative Diseases

Aging is the most significant and universal risk factor for developing neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s, Parkinson’s, and Huntington’s diseases. This risk increases disproportionately with age, but no one really knows why.

Now a team of scientists from Northwestern University, Proteostasis Therapeutics, Inc. and Harvard University has uncovered some clues. The researchers are the first to find that the quality of protective genes called molecular chaperones declines dramatically in the brains of older humans, both healthy and not, and that the decline is accelerated even more in humans with neurodegenerative disease. The study will be published in the November 6th 2014 issue of the journal Cell Reports.

A release from Northwestern explains that molecular chaperones are a special set of highly conserved genes that watch over cells, keeping them and the entire organism healthy by preventing protein damage.

The researchers specifically found the decline in 100 genes, approximately one-third of all human molecular chaperone genes. Then, with additional studies, they winnowed that number down to 28 human genes specifically involved in age-associated neurodegeneration. These critical genes provide a basis for a biomarker, an early indicator of disease and a target for new therapeutics.

The release quotes Northwestern’s Richard I. Morimoto, one of the senior scientists on the study, as saying, “Imagine if we had biomarkers that tell doctors how you are doing in terms of aging, warning of any problems long before neurological deficits appear. This would be a remarkable tool, especially considering the increases in life expectancy in many parts of the world. Let’s say a person is age 50, but we see his molecular chaperones have declined and aren’t repairing proteins and cellular damage. The chaperones are acting more like age 85 or 90. That’s a sign that medical intervention could help.”

Morimoto is the Bill and Gayle Cook Professor of Biology in the Department of Molecular Biosciences and director of the Rice Institute for Biomedical Research in Northwestern’s Weinberg College of Arts and Sciences.

“Molecular chaperones really are the barrier we have between disease and no disease,” Morimoto said. “If this critical system declines, it leads to misfolded and damaged proteins, and eventually tissues become dysfunctional and die. If we can keep the chaperones healthy, we should be able to keep the person healthy.”

To zero in on the subnetwork of 28 key genes, the scientists combined genomic analysis of human brain tissue, from both healthy individuals and those with neurodegenerative diseases (Alzheimer’s, Parkinson’s and Huntington’s), with functional studies of C. elegans, a transparent roundworm. (The worm has a biochemical environment similar to that of human beings and is a popular research tool for the study of human disease.)