By Lori Maricle, College of Pharmacy
SPOKANE, Wash. – Repairing the brain’s “house-cleaning function,” which could help people with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS) and 100 other diseases, is the focus of recently funded research at Washington State University.
The work will make a point of including undergraduate researchers.
“Who wouldn’t want to help fight diseases like these?” said Travis Denton, a medicinal chemist at the WSU College of Pharmacy in Spokane. He was awarded $446,233 over three years from the National Institutes of Neurological Disorders and Stroke to investigate new drugs to treat neurological disorders related to autophagic dysfunction.
Autophagy is a process that recycles and clears out old or damaged particles and proteins from cells.
“Autophagy helps defend against metabolic stress, maintains homeostasis and safeguards genomic stability. It’s the house-cleaning function of the brain,” said Denton.
For patients with neurologic disorders, autophagy doesn’t work properly, or at all.
“This would be as if the housekeeper – who typically comes over once every week – just stops coming over all together,” said Denton. “In the body, when this happens, cells begin to die and the system degenerates.
“My collaborator in this project, Dr. Kenneth Hensley at the University of Toledo, has uncovered a fundamentally new way to activate autophagy,” said Denton. “The new chemicals being prepared in our lab are developed to selectively activate autophagy – recruiting the housekeepers back to the brain and, hopefully, regenerating the system.”
The Hensley compound mimics the natural brain metabolite lanthionine ketimine (LK) that activates autophagy by:
• Keeping abnormal proteins from building up and potentially shutting down major organs (heart, liver and nervous system, to name a few)
• Protecting the brain’s functions of learning and memory against neurotransmitter toxicity
• Activating or increasing the activity of proteins that promote the initial growth, maintenance and survival of brain neurons
• Enhancing the movement of proteins, lipids and other cell parts through the cytoplasm of cell bodies.
ALS, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury and aging differ fundamentally but all share the element of autophagic dysfunction.
“This new funding means we can start the medicinal chemistry investigation into the nature of the compound’s membrane (brain) permeability, esterase liability and overall effectiveness as a drug,” said Denton.
In addition, “one of the goals of this proposal is to give undergraduate students the opportunity to experience all that graduate school in the biomedical sciences at an R1 university setting has to offer,” he said.
While the WSU College of Pharmacy is primarily a professional (Pharm.D.) and graduate education (Ph.D.) college, Denton’s lab has agreements with Gonzaga University, Whitworth University and Eastern Washington University so undergraduate students can obtain course credits.
Getting students into the lab where they can see the real-world application of the basic chemistry that is still fresh in their memory does a lot to spark their interest, said Denton.
“Being able to create a drug that could help, or cure, a devastating disease like ALS is what turned me from pre-med as an undergraduate to studying medicinal chemistry,” he said.
The research complements WSU’s Grand Challenges initiative stimulating research to address some of society’s most complex issues. The work is particularly relevant to the challenge “Sustaining Health: The Uncompromising Pursuit of Healthier People and Communities,” including its theme of changing the course of disease. The grant number is R15NS093594.