RESUMO
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.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Curcumina/farmacologia , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismo , 1-Metil-4-fenilpiridínio/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Células HeLa , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/prevenção & controle , Neurônios/citologia , Neurônios/efeitos dos fármacos , Células PC12 , Doença de Parkinson/genética , Doença de Parkinson/prevenção & controle , Interferência de RNA , Ratos , Transdução de Sinais/efeitos dos fármacos , alfa-Sinucleína/metabolismoRESUMO
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in older individuals with specific neuropsychiatric symptoms. It is a proteinopathy, pathologically characterized by the presence of misfolded protein (Aß and Tau) aggregates in the brain, causing progressive dementia. Increasing studies have provided evidence that the defect in protein-degrading systems, especially the autophagy-lysosome pathway (ALP), plays an important role in the pathogenesis of AD. Recent studies have demonstrated that AD-associated protein aggregates can be selectively recognized by some receptors and then be degraded by ALP, a process termed aggrephagy. In this study, we reviewed the role of aggrephagy in AD development and discussed the strategy of promoting aggrephagy using small molecules for the treatment of AD.
