Genetic and Chemical Activation of TFEB Mediates Clearance of Aggregated α-Synuclein

Aggregation of a-synuclein (alpha-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of alpha-syn aggregates results from aberrant accumulation of misfolded alpha-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway. In this study, we investigated the role of transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in preventing the accumulation of alpha-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated alpha-syn by inducing autophagic clearance of alpha-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-beta-cyclodextrin promotes autophagic clearance of aggregated alpha-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of alpha-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of alpha-syn aggregates.