Tau Isoform Expression in FTDP-17

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Filamentous aggregates of hyperphosphorylated tau are the signature brain lesions of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP 17), an inherited tauopathy with diverse, phenotypes caused by different tau gene mutations. Tau is a microtubule (MT) binding protein that promotes tubulin polymerization into MTs and stabilizes MTs. The adult human brain contains six tau isoforms, half with 3 3R isoforms) and half with 4 Cterminal MTbinding repeats (4R isoforms) generated by alternatively splicing of exon 10 (E 10). Tau gene mutations cause FTDP 17 by impairing E 10 alternative splicing or tau functions. A puzzling aspect of the FTDP 17 syndromes is that different tau mutations damage selected subtypes of neurons and glia. Our first hypothesis is that this selective vulnerability may reflect cell type specific perturbations of tau isoforms to cause varied phenotypes. To test this hypothesis, we will determine mRNA expression profiles of tau isoforms in normal brain cell subpopulations. Although the ratio of 3R to 4R tau is 1:1 in normal human brain, it has never been determined in subpopulations of neurons and glia. In, Aim 1, we will microdissect neurons and glia from paraffinembedded tissue sections of control brains, perform linear amplification on extracted RNA followed by quantitative realtime RTPCR to measure the relative levels of each tau isoform mRNA. In Aim 2, we will similarly study the same neuronal and glial cell populations in FTDP 17 brains. Correlation of these data with disease phenotypes will clarify mechanisms of FTDP1 7. Since FTDP1 7 mutations produce different phenotypes in the same kindred, a second hypothesis proposes that altered expression of a second gene, which interacts with the tau gene or protein, influences development of phenotypic manifestations of FTDP 17 in different affected family members. Aim 3 tests this hypothesis by examining the differential expression of candidate genes (i.e. those involved in splicing, RNA stability, tau function, other cellular processes) between affected and unaffected FTDP 17 brain regions and control brains using custommade cDNA macroarrays. The completion of these Aims will advance understanding of FTDP 17 and related tauopathies, and may provide new targets for diagnosis and therapeutics.