Pathogenic Role of Tubulin Tyrosine Ligase and Delta-2 Tubulin in Alzheimer's Disease

Background The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials to the cells, providing them with energy and keeping them healthy. The tau protein helps keep these tracks straight. However, in Alzheimer’s and other brain diseases like frontotemporal dementia, Pick’s disease and over 20 other brain diseases, the shape of tau protein becomes modified or “misfolded” and this could contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. Tau also helps maintain structures that gives cells their shape. The structure is comprised of a dynamic protein called “tubulin.” Several specialized proteins, called “enzymes,” work together to shorten or lengthen tubulin (cut tubulin) in response to a cell’s needs. However, studies show that one variation of tubulin, called delta-2 tubulin, once cut can no longer be modified to assist in the functions of the cell. Studies also show that delta-2 tubulin can accumulate in the brain in Alzheimer’s and may be associated with the formation of the tau tangles. Dr. Julie Parato will study how changes in the functionality of the enzymes that cut tubulin may impact brain changes observed in Alzheimer’s. Research Plan Dr. Parato and colleagues will study an enzyme that cuts tubulin- called “tubulin tyrosine ligase (TTL),” to determine if it might be associated with tau tangles or other aspects of the nerve cell damage observed in Alzheimer’s. First, the researchers will use brain tissue from individuals who had Alzheimer’s to measure the activity of this enzyme and other enzymes associated with cutting tubulin. Additionally, the researchers will study the activity of this enzyme by creating nerve cells from iPSCs (induced Pluripotent Stem Cells), a special type of stem cell from human adult tissue. iPSCs can be programmed to grow into any type of cell in the human body. They will then evaluate whether changes in the enzymes may impact the formation of tau tangles in these nerve cells. Furthermore, by genetically engineering nerve cells to lack TTL or to have increased levels of delta-2 tubulin, Dr. Parato’s team will evaluate how these changes may impact nerve cell function and abnormal tau accumulation. Finally, the researchers will evaluate whether changes to the enzymes that cut tubulin may impact a string of subsequent biological events by studying the functionality of a protein (AMPK) that senses stress inside nerve cells. Dr. Parato aims to study if this could be further associated with the formation of tau tangles and nerve cell damage.