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2015 Grants - Yamamoto
Functional Analysis of an Alzheimer’s Disease-Associated Mutation in TM2D3
Shinya Yamamoto, D.V.M., Ph.D.
Baylor College of Medicine
2015 New Investigator Research Grant
How do variations in the gene for TM2D3 influence the risk for Alzheimer’s disease?
Recent studies have found that people with a certain variation in a gene called TM2 domain-containing 3 (TM2D3) have an increased risk for developing Alzheimer’s disease. However, the function of this gene is unknown and it is not yet understood how these variations might lead to Alzheimer’s disease.
To gain insight into the function of the human TM2D3 gene, Dr. Shinya Yamamoto, D.V.M, Ph.D., and colleagues have turned to fruit flies to study nerve cells. The fruit fly gene for TM2D3 is very similar to the human gene and therefore may provide important clues about its function. In flies, TM2D3 likely influences the action of a protein called gamma-secretase which is involved in the processing of another protein called amyloid precursor protein. In humans, altered processing of the amyloid precursor protein leads to the production of beta-amyloid which can form amyloid plaques, a hallmark Alzheimer’s disease in the brain.
Dr. Yamamoto’s team will investigate the normal function of the human TM2D3 gene to better understand how abnormal variations may be related to Alzheimer’s disease. The researchers will utilize fruit flies as model organisms for studying TM2D3. This is possible because the human TM2D3 gene can substitute for the fly gene. In addition, the researchers can perform a series of powerful genetic experiments in fruit flies that would be very difficult to do in mice or humans. Dr. Yamamoto’s group will first focus on understanding if and how human TM2D3 affects gamma-secretase and protein processing. They will use diverse technologies to look at these changes in flies carrying the normal human TM2D3 gene versus flies carrying the version of the gene that increases Alzheimer’s risk.
This work will improve our understanding of the role of the TM2D3 gene in brain function and help reveal how alterations in this gene may promote Alzheimer’s disease. Additionally, the novel methods utilized in these fruit fly studies may be broadly applicable to investigating the function of other Alzheimer’s risk genes about which there is little biological information. Most importantly, this work may reveal novel genetic targets for the future development of treatments to prevent, slow or treat Alzheimer’s disease.