Optical induction of autophagy via Transcription factor EB (TFEB) reduces pathological tau in neurons

被引:16
作者
Binder, Jessica L. [1 ]
Chander, Praveen [2 ]
Deretic, Vojo [1 ,3 ]
Weick, Jason P. [2 ]
Bhaskar, Kiran [1 ]
机构
[1] Univ New Mexico, Dept Mol Genet & Microbiol, Hlth Sci Ctr, Albuquerque, NM 87131 USA
[2] Univ New Mexico, Dept Neurosci, Hlth Sci Ctr, Albuquerque, NM 87131 USA
[3] Univ New Mexico, Hlth Sci Ctr, Autophagy Inflammat & Metab Ctr Biomed Res Excell, Albuquerque, NM 87131 USA
来源
PLOS ONE | 2020年 / 15卷 / 03期
基金
美国国家卫生研究院;
关键词
ALZHEIMERS-DISEASE; PHOSPHORYLATED TAU; GENE-EXPRESSION; PROTEIN-TAU; ACTIVATION; BRAIN; LIGHT; DEMENTIA; BINDING; TARGET;
D O I
10.1371/journal.pone.0230026
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:19
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