Genetic and Chemical Activation of TFEB Mediates Clearance of Aggregated α-Synuclein
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Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson’s disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-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 α-syn aggregates in human neuroglioma cells. We found that TFEB overexpression reduces the accumulation of aggregated α-syn by inducing autophagic clearance of α-syn. Furthermore, we showed that pharmacological activation of TFEB using 2-hydroxypropyl-β-cyclodextrin promotes autophagic clearance of aggregated α-syn. In summary, our findings demonstrate that TFEB modulates autophagic clearance of α-syn and suggest that pharmacological activation of TFEB is a promising strategy to enhance the degradation of α-syn aggregates.
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Kilpatrick, Kiri, Zeng, Yimeng, Hancock, Tommy, et al.. "Genetic and Chemical Activation of TFEB Mediates Clearance of Aggregated α-Synuclein." PLoS ONE, 10, no. 3 (2015) Public Library of Science: e0120819. http://dx.doi.org/10.1371/journal.pone.0120819.