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    Modeling the in vitro aggregation of 4R tau isoforms for a comparative study of FTDP-17 mutants

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    Issue Date
    2017-12-31
    Author
    Yamini, Fnu
    Publisher
    University of Kansas
    Format
    111 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular Biosciences
    Rights
    Copyright held by the author.
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    Abstract
    Tau is a microtubule binding protein typically found in neuronal axons. In an adult human brain, six isoforms of tau are generated by alternate mRNA splicing. These isoforms of tau differ from each other either based on the number of N-terminal inserts and/or the number of microtubule binding repeats. Tau is also closely related to a group of progressive neurodegenerative disorders together known as tauopathies. In these disorders, tau gets misfolded and its ability to stabilize microtubules gets compromised. Monomers of tau then begin to polymerize to form pathologic aggregates. These aggregates of tau get deposited in the patient’s brain and are closely related to neuronal dysfunction and death of neurons. Although the aggregation of tau is a central event for the majority of these tauopathies, the precise neuropathologic and clinical presentation differs between these diseases. The age of onset, area of brain affected, morphology of tau aggregates and the isoform of tau deposited as aggregates are a few of the distinguishing features between these tauopathies. The underlying mechanism of tau aggregation as well the mechanisms leading to these differences are not well understood. Before effective therapies can be devised to stop the process of tau aggregation, the mechanisms influencing this process need to be understood. One of the ways employed to gain a mechanistic understanding of this process is by using an in vitro aggregation model. In this model, an inducer molecule is used to generate aggregates of recombinantly produced tau and various mechanisms influencing the process of aggregation can be studied. This method has been successfully used to model aggregation of the longest isoform of tau called the 2N4R isoform, however the applicability of this methodology to isoforms missing one or more of the N-terminal inserts has proven to be challenging. In this study, we optimized the process of in vitro aggregation for these isoforms. We discovered that the major differences between the isoelectric points of the N-terminal region of these tau isoforms leads to behavioral changes between these isoforms. This observation favors the notion that the isoforms of tau might also get disproportionately influenced by disease related mechanisms leading to their differential deposition as aggregates in certain tauopathies. On the contrary, the isoforms of tau have often been used interchangeably for the design of many studies. Using the optimized aggregation conditions, we investigated the effects of one such disease related changes in tau on various isoforms of tau. We performed a comparative study of autosomal dominant mutations in tau selected from three different regions and investigated their effects on the aggregation propensity and microtubule stabilizing properties of tau. We found subtle but significant differences in the effect of these mutations on various tau isoforms for all three selected mutants. Overall, these findings have opened up new avenues for the study of aggregation of various tau isoforms. They also helped us understand the differences between tau isoforms as well as how disease related changes could potentially influence the tau isoforms differentially.
    URI
    http://hdl.handle.net/1808/27023
    Collections
    • Molecular Biosciences Dissertations and Theses [273]
    • Dissertations [4321]

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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