The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases

Abstract

The autophagy‐lysosomal pathway (ALP) is involved in the degradation of protein aggregates and damaged organelles. Transcription factor EB (TFEB), a major regulator of ALP, has emerged as a leading factor in addressing neurodegenerative disease pathology, including Alzheimer's disease (AD), Parkinson's disease (PD), PolyQ diseases, and Amyotrophic lateral sclerosis (ALS). In this review, we delineate the regulation of TFEB expression and its functions in ALP. Dysfunctions of TFEB and its role in the pathogenesis of several neurodegenerative diseases are reviewed. We summarize the protective effects and molecular mechanisms of some TFEB‐targeted agonists in neurodegenerative diseases. We also offer our perspective on analyzing the pros and cons of these agonists in the treatment of neurodegenerative diseases from the perspective of drug development. More studies on the regulatory mechanisms of TFEB in other biological processes will aid our understanding of the application of TFEB‐targeted therapy in neurodegeneration.

Transcriptional Signatures and Network-Based Approaches Identified Master Regulators Transcription Factors Involved in Experimental Periodontitis Pathogenesis

“…An exemplary case is the transcription factor EB (TFEB), recognized as a master regulator of the autophagy-lysosomal biogenesis pathway, which stimulates cell clearance. TFEB has emerged as a therapeutic modulator in lysosomal storage diseases [90,91] and a promising target in the treatment of neurodegenerative disorders (ND), such as Alzheimer's disease and Parkinson's diseases [92,93]. Similarly, Forkhead Box O3 (FOXO3a) is regarded as a regulator in autoimmune disorders.…”

Unraveling Lineage Roadmaps and Cell Fate Determinants to Postnatal Neural Stem Cells and Ependymal cells in the Developing Ventricular Zone

“…Recent studies have shown that Tfeb plays crucial roles in the NDD pathogenesis. Dysregulation of Tfeb expression, nuclear localisation and transcriptional activity has been observed in various NDDs, including Alzheimer’s Disease, Parkinson’s disease and Huntington’s disease [74]. The activation of Tfeb has been widely proven to ameliorate the pathological protein aggregates in neurons [66, 74–76].…”

“…Dysregulation of Tfeb expression, nuclear localisation and transcriptional activity has been observed in various NDDs, including Alzheimer’s Disease, Parkinson’s disease and Huntington’s disease [74]. The activation of Tfeb has been widely proven to ameliorate the pathological protein aggregates in neurons [66, 74–76]. It promotes the removal of these aggregates through the up-regulation of lysosomal biogenesis and autophagy.…”

“…The activation of Tfeb has been widely proven to ameliorate the pathological protein aggregates in neurons [66,[74][75][76]. It promotes the removal of these aggregates through the up-regulation of lysosomal biogenesis and autophagy.…”

Design and validation of a reporter mouse to study the dynamic regulation of TFEB and TFE3 activity through in vivo imaging techniques

“…The overlapping pattern of gene expression shared with other families of transcription factors and the resulting modulation of genes involved in various stress pathways partly explains the diverse therapeutic effects achieved by activating or inhibiting MiT/TFE factors. TFEB or TFE3 activation has been shown to be beneficial for improving neuronal health [ 62 ], insulin sensitivity [ 6 ], and cardiomyocyte survival during ischemia-reperfusion damage in the heart [ 63 ]. On the contrary, inhibiting TFEB and TFE3 activity has demonstrated beneficial effects by reducing cancer cell viability and increasing their susceptibility to anticancer therapies [ 31 , 64–66 ].…”