2023 Alzheimer's Association Research Grant (AARG)
Mitochondrial Protein Quality Control and Ca2+ Flux in Alzheimer's Disease
How does calcium movement inside cells change during Alzheimer’s?
Dhanendra Tomar, Ph.D.
Wake Forest University Health Sciences
Winston-Salem, NC - United States
Background
Mitochondria are specialized structures inside cells that make energy for cells. There are several molecules inside mitochondria that support this process. These include calcium molecules that flow in and out of mitochondria and the proteins that help mitochondria take in calcium, which are known as mitochondrial calcium uptake proteins, or “MICUs.” The functions of MICUs are tightly controlled by “quality-control” proteins that are also found inside mitochondria.
Previous work by Dr. Dhanendra Tomar and colleagues has shown that individuals with Alzheimer’s have especially low levels of MICUs inside their mitochondria. Among MICUs that are present, many degrade quickly. Dr. Tomar has also found that MICUs directly interact with a quality control protein, known as CLPB, which appears to contribute to low MICU levels during Alzheimer’s. Low MICU levels could affect calcium or energy levels inside cells and lead to brain cell changes seen in Alzheimer’s.
Research Plan
Dr. Tomar will explore whether CLPB might be contributing to the degradation of MICUs in Alzheimer’s, to understand whether CLPB might be targeted therapeutically to restore healthy calcium levels inside mitochondria. First, Dr. Tomar’s team will study cells growing inside laboratory dishes that have been genetically engineered to lack the gene that makes the CLPB protein. The researchers will provide the cells with pieces of the CLPB protein and use specialized microscopes to track the movement within mitochondria. This process will allow Dr. Tomar to see exactly which parts of the CLPB protein interact with MICUs, and where these interactions occur inside mitochondria to better understand which portions of CLPB might be most important therapeutically.
Next, Dr. Tomar’s team will use sophisticated sensors to measure calcium flow in and out of the cells lacking CLPB, and the activity of small pores in the surfaces of mitochondria which calcium molecules flow through. The researchers will also identify any physical changes that occur in mitochondria collected from cells to understand how CLPB might contribute to changes in mitochondria that occur in Alzheimer’s. Finally, the team will monitor cognitive changes in genetically engineered Alzheimer’s-like mice that lack the gene encoding CLPB. The researchers will measure the health of the mitochondria in the brain cells and levels of beta-amyloid protein in the brains of the mice, which is a hallmark protein in Alzheimer’s.
Impact
Results from this study could clarify the molecular underpinnings of changes in mitochondria that can occur in Alzheimer’s. The study may also help determine whether a specific protein found in mitochondria, CLPB, might be an important therapeutic target for drugs designed to restore healthy mitochondria function during Alzheimer’s.