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2008 Grants - Liu
Involvement of Dyrk1A in ASF-Regulated Alternative Splicing of Tau Exon 10
Fei Liu, Ph.D.
Research Foundation for Mental Hygiene, Inc. at
New York State Institute for Basic Research
Staten Island, New York
2008 New Investigator Research Grant
Tau is a protein important for the maintenance of nerve cell structure. For reasons that are not well understood, tau can become abnormal and form neurofibrillary tangles, one of the characteristic features of Alzheimer pathology. Six forms of tau are known in humans, although they are all coded by the same gene. The different forms arise from different ways the decoded gene is assembled, a process known as alternative splicing. Exon 10 refers to a region of the gene that is included in some forms of tau but not in others.
Normally, cells tightly regulate the proportion of tau proteins that include exon 10. In some individuals, however, genetic mutations disrupt this balance. These mutations are associated with neurofibrillary tangles and some forms of dementia. Mutations or changes in the expression of other genes can also disrupt the balance of tau forms and cause similar pathological changes.
Fei Liu, Ph.D., and colleagues have recently found that individuals with Down syndrome have a disrupted balance of tau protein forms. This observation may explain the fact that these individuals almost always develop neurofibrillary tangles at a young age. Dr. Liu and colleagues are studying the molecular mechanisms that explain these changes in tau expression. They have focused on a protein called alternative splicing factor (ASF) that binds to special regions in exon 10 of the tau gene, controlling whether this exon is included in the final protein. They have also identified another protein called Dyrk1A that they believe may interact with ASF. Dyrk1A is of particular interest because its gene resides at a location known to be involved in Down syndrome.
Dr. Liu and colleagues plan to extend their studies of the proteins involved in the regulation of exon 10 in an effort to understand the mechanisms leading to the formation of neurofibrillary tangles. These studies may improve our understanding of this pathologic feature of Alzheimer's disease and may indentify potential targets for therapies to treat the disease.