Tau is a microtubule (MT) associated protein (MAP) that is found aggregated into straight (SF) or paired helical (PHF) filaments within neurofibrillary tangle deposits in Alzheimer's disease (AD) and other neurodegenerative disorders. Mutations in the gene encoding tau are associated with the hereditary syndrome FTDP-17 (frontotemporal dementia and Parkinsonism linked to chromosome 17) indicating that tau plays a causative role in the pathogenesis of this and possibly other diseases such as AD. Many of the FTDP-17 linked mutations fall within the MT binding domain (MBD) of tau, a region that contains, depending on the isoform, three or four pseudo-repeats (3R vs. 4R) of a 31 to 32 residue MT interaction motif. These mutations disrupt tau-MT interactions and tau-promoted MT assembly, and several also enhance tau PHF formation in vitro. A different class of FTDP-17 associated mutations influence tau mRNA splicing and alter the ratio of 4R to 3R tau isoforms in vivo, which can both modulate the normal functions of tau and enhance tau aggregation by altering the relative populations of free and MT-bound isoforms. Thus, tau mutations may exert pathogenic effects by interfering with tau function, by enhancing tau aggregation, or by both means. Tau is intrinsically unstructured when free in solution but undergoes structural transitions upon binding to MTs, upon filament formation, and upon associating with lipid membranes. Residual structure in free tau may play an important role in mediating these various intermolecular interactions. We propose to characterize, at high resolution, the structural and dynamic properties of tau in its free state using NMR spectroscopy. We will also elucidate in detail the structure of detergent micelle associated tau and the topology of lipid vesicle and MT-bound tau. We will probe the effects of FTDP-17 linked mutations on the structural properties of free, lipid-associated and MT-bound tau and will use newly designed mutations to elucidate the structural basis for these intermolecular interactions. Our studies will focus on 3R and 4R forms of the tau MBD. The results will clarify the molecular mechanisms underlying both normal tau function and tau induced neurodegeneration and may suggest strategies for developing new therapeutics. This work may also have broader implications for understanding and treating other protein aggregation diseases.
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