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2016 Grants - Lee, D
Modulation of GPRC6a Signaling to Mitigate Tauopathies
Daniel Carl Lee, Ph.D.
University of South Florida
2016 Alzheimer’s Association Research Grant to Promote Diversity (AARG-D)
Can inhibiting the activity of a protein called GPRC6a reduce the formation of tau tangles in the brain?
Tau is a protein that normally functions to help cells maintain their structure and transport nutrients. In several neurodegenerative diseases, including Alzheimer’s disease, tau accumulates and forms abnormal structures known as tau tangles. Collectively, these diseases are known as tauopathies. Scientists do not yet understand what causes tau tangles to form.
One possible trigger for cells to begin forming tau tangles is alterations in the levels of a molecule known as L-arginine. L-arginine is an important amino acid (chemical building block of proteins), but recent studies suggest that pathways for its use in the brain may become impaired during Alzheimer’s disease leading to the formation of tau tangles. GPRC6a is a protein on the surface of nerve cells that acts as a “receptor” for L-arginine; abnormal activation of GPRC6a may contribute to tau accumulation in nerve cells, but the molecular mechanisms are not yet understood.
Daniel Carl Lee, Ph.D., and colleagues have proposed a series of studies to explore the role of GPRC6a in the formation of tau tangles. They will study mice genetically engineered to lack GPRC6a in the brain and determine if this reduces abnormal tau accumulation and improves the animals’ cognitive function. The researchers hypothesize that blocking GPRC6a will trigger a cellular process called “autophagy” which helps remove abnormal tau from the brain. The researchers will also treat nerve cells growing in laboratory dishes with novel drugs designed to selectively inhibit GPRC6a activity and determine if they can promote the breakdown and clearance of tau tangles.
The results of these studies could shed new light on the molecular mechanisms underlying abnormal build-up of tau in the brain. Importantly, this research will help determine if GPRC6a is a possible target for the development of drugs to prevent the formation of tau tangles in the brain.