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PLoS One. 2015 Mar 19;10(3):e0120819. doi: 10.1371/journal.pone.0120819. eCollection 2015.

Genetic and chemical activation of TFEB mediates clearance of aggregated α-synuclein.

Author information

1
Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas, United States of America.
2
Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas, United States of America; Department of Bioengineering, Rice University, Houston, Texas, United States of America; Department of Biochemistry and Cell Biology. Rice University, Houston, Texas, United States of America.

Abstract

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.

PMID:
25790376
PMCID:
PMC4366176
DOI:
10.1371/journal.pone.0120819
[Indexed for MEDLINE]
Free PMC Article

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