Functional and Pathological States of the Protein Tau Investigated with Solid-State NMR
Author(s)
Dregni, Aurelio J.
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Advisor
Hong, Mei
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The microtubule-associated protein tau is expressed at high levels in human brain, and its binding and stabilization of microtubules is thought to play key roles in the maintenance of neurons. However, tau is found to pathologically aggregate into specific fibrillar structures in a number of neurodegenerative diseases, such as Alzheimer’s disease, which is the most common neurodegenerative disease in humans. Each disease is characterized by a specific fibril structure, conserved between patients of the same disease, and distinct between diseases. These pathological fibrillar aggregates of tau appear to spread in a prion-like manner throughout connected pathways in the brain and the extent of tau aggregates in brain is well correlated with observed neurodegeneration. Together, these findings indicate that these distinct tau structures are in some way fundamentally tied to each disease, and they may be part of the causative chain of each disease.
No mechanistic treatment for these tauopathies is currently available, prompting detailed study into the tau protein itself. It is unclear how the protein tau can aggregate into so many distinct but conserved structures: knowledge how the protein can be made to aggregate into specific structures in vitro would reveal what specific insults may cause aggregation in each disease. Recently, the rigid cores of the pathological fibrils from human brain have been well characterized by cryo-electron microscopy, however, little is known about the “fuzzy coat”, the disordered remaining of the protein that surrounds the small fibril core. The structure and dynamics of the disordered fuzzy coat may play key roles in modulating interactions between these pathological fibrils, and the cellular milieu, as well as any drug molecule applied to the fibrils. In addition, due to mixing of two protein isoforms, the Alzheimer’s disease fibril structure has primary sequence heterogeneity immediately outside of the rigid core. How these isoforms are mixed and the effects of this mixing is poorly understood, and these may play key roles in making AD the most common neurodegenerative disease in humans. Finally, the mechanism by which healthy tau binds to and stabilizes microtubules is poorly understood, and a detailed understanding of tau’s functional role is required if we are to avoid interfering with its
Solid-state NMR is uniquely suited to studies of the protein tau in its heterogeneously dynamic states. In this thesis, I describe in detail the theory behind magic-angle spinning solid state NMR, and then present five manuscripts in which I have developed and applied solid-state NMR experiments to answer the specific biological questions I pose above by studying a diverse array of states of the protein tau. I hope that research built on these studies may someday help to design mechanistic therapies that can slow or even prevent these terrible and yet very common neurodegenerative diseases.
Date issued
2022-05Department
Massachusetts Institute of Technology. Department of ChemistryPublisher
Massachusetts Institute of Technology