Biomedical Sciences ETDs

Publication Date

Summer 7-10-2019

Abstract

To this day, there is no cure for Alzheimer’s disease (AD) and related dementias (ADRD). With the daunting rise at an exponential rate of ADRD burden and related deaths, the necessity to find a new line of attack is vital. Pathological accumulation of microtubule associated protein tau in neurons is a major neuropathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Attempts have been made to promote clearance of pathological tau (p-Tau) from neurons via autophagy. Transcription factor EB (TFEB) has shown to clear p-Tau from neurons via autophagy. However, sustained TFEB activation and autophagy can create burden on cellular bioenergetics and can be deleterious. Here, we engineered previously described two-plasmid systems of Light Activated Protein (LAP) from bacterial transcription factor – EL222 and Light Responsive Element (LRE) to encode TFEB. Upon blue-light (465nm) illumination, the conformation changes in LAP induced LRE-driven expression of TFEB, its nuclear entry, TFEB-mediated expression of autophagy-lysosomal genes and clearance of p-Tau from neuronal cells and AD patient-derived human iPSC-neurons. Turning the blue-light off reversed the expression of TFEB-target genes and prevented p-Tau clearance. Together, these results suggest that optically regulated TFEB expression unlocks the potential of opto-therapeutics to treat AD and other dementias.

Keywords

optogenetics, tauopathies, gene expression, autophagy, Alzheimer's Disease

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Kiran Bhaskar, PhD

Second Committee Member

Jason Weick, PhD

Third Committee Member

Nora Perrone-Bizzozero, PhD

Fourth Committee Member

Jonathan Brigman, PhD

Fifth Committee Member

Vojo Deretic, PhD

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