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Liver kinase B1 modulation of tau expression and phosphorylation

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posted on 2022-08-17, 03:01 authored by Miheer Baburao Sabale

Alzheimer’s disease (AD) is the most common cause of dementia and macroscopically, AD brains present with moderate cortical atrophy. However, atrophy is not exclusive to AD and a positive diagnosis requires the presence of both insoluble extracellular amyloid β plaques and intracellular neurofibrillary tangles (NFT’s) comprised of paired helical fragments of tau (PHF-tau). The normal function of tau is to localize in the axonal compartment and modulate the assembly and organization of microtubules. In AD, tau is abnormally phosphorylated at both physiological and pathological sites causing it to detach from the microtubule network, change localization and associate with novel binding partners. Mounting evidence suggests that LKB1, traditionally classed as a tumor suppressor gene and a metabolic master kinase, also modulates tau phosphorylation. Of specific interest to this study are the LKB1 mediated phosphorylation of Ser262 and Ser356 located in the microtubule binding domain of tau. This domain regulates tau’ affinity to microtubules and aberrant phosphorylation of these sites is thought to initiate a cascade of subsequent phosphorylation by other kinases. The present study demonstrates LKB1 mediated tau phosphorylation at Ser262 and Ser356 under simulated hypoglycemic conditions and a previously unknown role of LKB1 in regulating tau expression. It expands on available research by demonstrating the effects of kinase-sufficient and kinase-deficient LKB1 on the expression of phosphorylation-mimetic and phospho-inhibiting tau variants and provides a roadmap for future experiments to study these interactions in greater detail.

History

Table of Contents

1. Introduction -- 2. Methods -- 3. Results -- 4. Discussion -- References

Notes

A thesis submitted in partial fulfillment of the requirements for the degree of Master of Research

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Degree

Thesis (MRes), Macquarie University, Faculty of Medical and Health Sciences, 2020

Department, Centre or School

Department of Biomedical Sciences, Dementia Research Centre

Year of Award

2020

Principal Supervisor

Lars Ittner

Additional Supervisor 1

Yazi Ke

Rights

Copyright: Miheer Sabale Copyright disclaimer: https://www.mq.edu.au/copyright-disclaimer

Language

English

Extent

74 pages

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