Vacuolar Tauopathy

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Rare genetic causes of human disease have the potential to reveal mechanistic insights into more common sporadic disease. Rare mutations in MAPT, the gene for the neuronal cytoskeleton tau protein, cause familial tauopathies that typically manifest clinically as frontotemporal dementia. Tauopathies are a group of fatal neurologic diseases, including Alzheimer's disease, where neurodegeneration is the result of accumulation of pathologic tau protein aggregates in the form of neurofibrillary tangles, Pick bodies, or glial inclusions. MAPT mutations are the only known cause of autosomal dominant primary tauopathy. We have identified a previously undescribed autosomal dominant form of frontotemporal degeneration with tau inclusions associated with a novel genetic mutation in a highly conserved, essential gene. We propose three specific aims to understand the basic molecular mechanisms by which this gene mutation leads to tau pathology. We will perform studies to determine how this genetic mutation alters tau interactions and aggregation in vitro and in cultured cells. We will extend these findings to determine the effects of this gene mutation on endosomal function to determine whether this gene mutation affects intracellular seeding of tau aggregates. Finally, we will test the effects of this genetic mutation of tau transmission in mice to determine whether this gene mutation enhances tau virulence in vivo. Together, these mechanistic studies will elucidate basic mechanisms which promote tau pathology, thereby validating a novel therapeutic target for future development of novel anti-tau therapies.