Date of Award

Summer 8-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Prion-like propagation of tau aggregation may underlie the stereotyped progression of pathology along neuronal networks in neurodegenerative tauopathies such as Alzheimer’s disease. It has become increasingly clear that unique conformations (“strains”) of prion protein (PrP) link aggregate structure to clinical phenotypes in human prion diseases. Intriguingly, vast phenotypic diversity in pathological and clinical presentation is also observed in tauopathies. The mechanisms that account for this phenotypic diversity are completely unknown. During my dissertation work, I put forward and tested the hypothesis that distinct tau amyloid conformations (or “strains”) are responsible for unique tauopathies. First, I found that in experimental models, tau acts as a prion, replicating distinct strains in vitro and in vivo. I observed that tau indefinitely propagates distinct amyloid conformations in a clonal fashion in cell culture. In collaborative work, I found that two tau strains induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Remarkably, tau from these mice re-created the original strains upon re-introduction to cultured cells. Second, I created a panel of tau prion strains, which have remarkably divergent biochemical and cell biology properties and cause unique patterns of pathology and rates of progression in vivo. Finally, I used my cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with distinct strains. Tau thus demonstrates essential characteristics of a prion. This likely accounts for the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.

Language

English (en)

Chair and Committee

Conrad C. Weihl

Committee Members

Jan Bieschke, Marc I. Diamond, Timothy M. Miller, Heather L. True-Krob

Comments

Permanent URL: https://doi.org/doi:10.7936/K78W3BQC

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