Our long term goal is to understand the pathogenesis of a novel neurodegenerative disease in a family harboring a previously undescribed mutation. This family is afflicted with frontotemporal dementia (FTD), inherited in an autosomal dominant pattern. The neuropathology associated with this mutation is comprised of cytoplasmic vacuolization of neocortical neurons and Alzheimer?s disease-like tau protein aggregation. This pathology differs from any pathology described in the literature. Furthermore, this mutation represents the only FTD causing mutation associated with tau pathology outside of mutations in the tau gene itself. The first step in understanding the pathogenesis of this novel neurodegenerative disease is to understand the biochemical effect of this mutation. We hypothesize that this mutation disrupts critical protein structure leading to protein loss-of-function.
Specific Aim 1 will determine the biochemical structure of this mutant protein. We will use a combination of computational modeling and fluorometric imaging to understand how this mutation differs from wild type and other disease associated mutants of this protein.
Specific Aim 2 will determine the biochemical function of this mutant protein. We will use biochemical assays to characterize the enzymatic activity, substrate binding profile, and interaction with pathologic tau fibrils. Through our studies, we will begin to understand the pathogenesis of this novel neurodegenerative disease and gain insight on a new mechanism for Alzheimer?s disease pathology.
We aim to understand the pathogenesis of a novel neurodegenerative disease in a family harboring a previously undescribed mutation. This mutation is associated with cytoplasmic vacuolization of neocortical neurons and Alzheimer?s disease-like tau protein aggregation. This proposal would provide insight on the mechanism of pathogenesis of a novel disease, illustrate how this mutation is uniquely causing tau pathology, and potentially provide additional therapeutic targets for Alzheimer?s disease.