Abstract
Pathological accumulation of microtubule associated protein tau in neurons is a major neuropathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Several attempts have been made to promote clearance of pathological tau (p-Tau) from neurons. 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 modified 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 (465 nm) 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 attenuated p-Tau clearance. Together, these results suggest that optically regulated TFEB expression unlocks the potential of opto-therapeutics to treat AD and other dementias.
Highlights
Among various microtubule-associated proteins (MAPs), tau predominately localizes to axons where it binds to microtubules
We demonstrate the utility of an optical system to transiently regulate expression of Transcription factor EB (TFEB), which is a master transcriptional regulator of autophagy to reduce the load of pathological forms of tau on neurons
Our study described here is aimed towards achieving the transient ‘on/off’ activation/deactivation mechanism using a novel blue light inducible TFEB gene expression system that works well in mouse neuronal cell lines and human Alzheimer’s disease (AD) induced pluripotent stem cells (iPSC) derived into mature neurons
Summary
Among various microtubule-associated proteins (MAPs), tau (encoded by MAPT) predominately localizes to axons where it binds to microtubules. Tau is susceptible to many post-translational modifications [2], with phosphorylation being one of the well-studied modifications [3,4,5]. Tau’s affinity to microtubule decreases causing microtubules to undergo depolymerization [6], which has been the prevailing hypothesis, that such loss-of-function of tau contributes neurodegeneration [7,8]. These dissociated forms of tau can self-assemble into paired-helical filaments (PHFs) gaining further potential to aggregate as Neurofibrillary tangles (NFTs)–a classic neuropathological hallmark of Alzheimer’s.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
