Evaluating PLK2 as an Alzheimer's Therapy
Alzheimer’s disease (AD) is thought to be caused in part by the build-up of amyloid beta (Aβ) protein in the brain. Although the basic process that generates Aβ is well studied, an important unresolved question is what factors turn this process on and off. We have identified for the first time serine/threonine-protein kinase PLK2, an enzyme that in humans is encoded by the PLK2 gene, as a candidate factor that stimulates Aβ production. Here we will examine the role of PLK2 in disease progression using mouse models of Alzheimer's. These studies are critical for understanding the mechanisms underlying Alzheimer's and for advancing new targets for drug therapies.
Our project studies a novel protein, PLK2, that stimulates the production of pathogenic amyloid fragments and may be a potential new target for Alzheimer's therapeutics.
Alzheimer's disease (AD) is thought to be due to the build-up of amyloid protein in the brain (Aβ). An important unresolved question is what factors turn this process on and off? We have identified for the first time the protein PLK2 as a candidate factor that stimulates Aβ production and hypothesize that inhibition of PLK2 should slow down Aβ synthesis. In this proposal, we test this hypothesis and examine the role of PLK2 in disease progression using several complementary methods to inhibit PLK2 function. First, we employ two different small molecule inhibitors of PLK2 to ask if these compounds can slow disease progression in mouse models of AD. Second, we delete the PLK2 gene completely in mice to determine if genetic disruption of PLK2 can also dampen Aβ generation. Third, we analyze Aβ levels in a new transgenic mouse line we created using cutting-edge gene editing techniques in which we specifically disabled the ability of PLK2 to promote Aβ production.
In summary, the proposal addresses a novel hypothesis for AD pathogenesis which will advance basic understanding of mechanisms underlying AD and critically evaluate whether PLK2 represents a valid AD therapeutic target.
About the Researcher
Dr. Daniel T. S. Pak graduated from Harvard University with an BA degree in biochemistry in 1991. He received his PhD in molecular and cell biology from the University of California, Berkeley, in 1996. He was a postdoctoral fellow at Harvard Medical School and MIT Picower Center for Learning and Memory with Dr. Morgan Sheng, studying the molecular mechanisms of synaptic plasticity and cognition. Dr. Pak is currently an associate professor in the Department of Pharmacology and Physiology at Georgetown University Medical School, where he has continued his research on mechanisms of learning and memory and how these systems can become dysfunctional in memory disorders, including Alzheimer's. His studies focus primarily on the structure and function of glutamatergic synapses, utilizing a multidisciplinary approach spanning from molecules to animals.
I have always been fascinated by memory and trying to understand how the brain stores information in response to its environment. This remarkable feature is one of the crowning abilities of the human brain, yet one of the most mysterious. Thus, there is the challenge of the unknown that makes trying to understand how memory works an exciting adventure into a true frontier of science. Memories are also what makes us who we are, and gives us our very identities, as seen most dramatically when those memories are taken away in cognitive and memory disorders. Like so many others, my own family has been touched by this disorder when my father was diagnosed with Alzheimer's five years ago. I have witnessed firsthand the terrible debilitating effects of the disease on the patient and the toll that it takes on family members. These experiences have served to remind me of the critical importance of understanding what goes wrong in cognitive disorders and developing novel and more effective treatments for AD.
First published on: July 28, 2017
Last modified on: June 30, 2020