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Can a small change in DNA impact how the tau protein impacts disease progression?
Le Qi, Ph.D
University of California David Geffen School of Medicine
Los Angeles, CA - United States
Background
Tau is a protein that helps maintain the structure of healthy brain cells. However, the shape of tau protein can become modified or “misfolded,” leading to the accumulation of tau tangles, one of the hallmark brain changes in Alzheimer’s and other brain diseases. Accumulation of tau tangles can impact nerve cell communication as well as lead to nerve cell damage and death. Brain diseases believed to result from tau tangles are called “tauopathies”. Studies have found that changes in chromosomes, the organized structures of genetic material (DNA) in a cell, can lead to tauopathies, but the mechanisms are unknown. In initial findings, Dr. Le Qi and colleagues identified a change in a specific chromosome region, 17q21.31, that was associated with tauopathies.
Research Plan
For this study, Dr. Qi and team will build on their initial findings and examine the mechanisms linking 17q21.31 to tauopathies using human brain tissue. They will use brain tissue from individuals who had Alzheimer’s and cognitively unimpaired individuals who had variations in 17q21.31 for their study. Importantly, the researchers will include individuals of both European and African ancestry. Using sophisticated gene editing and sequencing techniques, they will study how variations in 17q21.31 impact genes associated with tauopathy.
Next, the team will use a specialized type of stem cell grown in a laboratory dish called iPSCs (induced Pluripotent Stem Cells) which can be programmed into any type of cell in the body and will make nerve cells, astrocytes (the “support” cells in the brain), and microglia (the primary immune cells in the brain). They will examine how variations in 17q21.31 impact genes associated with tauopathy in each cell type to identify the potential mechanisms by which this variation impacts tauopathy.
Impact
If successful, the results of this project could shed new light on the mechanisms that impact tauopathies and may identify new treatment strategies for brain diseases impacted by abnormal tau.
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