Abstract
TFEB (transcription factor EB), which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for Parkinson’s disease (PD). However, only several small-molecule TFEB activators have been discovered and their neuroprotective effects in PD are unclear. In this study, a curcumin derivative, named E4, was identified as a potent TFEB activator. Compound E4 promoted the translocation of TFEB from cytoplasm into nucleus, accompanied by enhanced autophagy and lysosomal biogenesis. Moreover, TFEB knockdown effectively attenuated E4-induced autophagy and lysosomal biogenesis. Mechanistically, E4-induced TFEB activation is mainly through AKT-MTORC1 inhibition. In the PD cell models, E4 promoted the degradation of α-synuclein and protected against the cytotoxicity of MPP+ (1-methyl-4-phenylpyridinium ion) in neuronal cells. Overall, the TFEB activator E4 deserves further study in animal models of neurodegenerative diseases, including PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, affecting around 6.2 million people in 2015 [1]
We examined the effects of E4 on the MTORC1 upstream kinase AKT, the phosphorylation of MTORC1, as well as substrate kinase P70S6K to determine whether E4 inhibits MTORC1 pathway to activate transcription factor EB (TFEB)
These results suggest that E4 activates TFEB via inhibiting the AKT-MTORC1 pathway
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, affecting around 6.2 million people in 2015 [1]. ALP, a cellular process for degrading misfolded cellular proteins and damaged organelles in lysosomes [6], has been proved to be tightly controlled by the transcription factor EB (TFEB) [9]. IInntthhiissssttuuddyy,, wwee cchhaarraacctteerriizzeedd aannootthheerr ccuurrccuummiinn ddeerriivvaattiivvee,, tteerrmmeedd EE44,, aass aannMMTTOORRCC11--ddeeppeennddeenntt aaccttiivvaattoorr ooff TTFFEEBB. Cpo
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