Optical induction of autophagy via Transcription factor EB (TFEB) reduces pathological tau in neurons
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ID: 270969
2020
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.
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binder2020plosoptical
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| Authors | Jessica L. Binder;Praveen Chander;Vojo Deretic;Jason P. Weick;Kiran Bhaskar; |
| Journal | PloS one |
| Year | 2020 |
| DOI | 10.1371/journal.pone.0230026 |
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