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.
Highlights
Parkinson’s disease (PD) is the most prevalent neurodegenerative movement disorder
Overexpression of S142A transcription factor EB (TFEB) via retroviral transduction of H4/α-syn-GFP cells with TFEB-S142A-3xFLAG was found to result in diffuse GFP signal and, importantly, to reduce ProteoStat dye binding to a larger extent than overexpression of wild type TFEB (WT TFEB)
The decrease in protein aggregation observed upon overexpression of WT TFEB is likely due to activation of TFEB induced by accumulation of αsyn aggregates, similar to what was previously reported in disease cells presenting deposition of storage material [28]
Summary
Parkinson’s disease (PD) is the most prevalent neurodegenerative movement disorder. It is characterized by the accumulation of proteinaceous cytoplasmic inclusions (Lewy bodies) in dopaminergic neurons [1]. The major component of Lewy bodies is α-synuclein (α-syn) [2], a natively unfolded 140 amino-acid protein with high propensity to misfold and aggregate [3]. The ubiquitin-proteasome system (UPS) provides the primary route for degradation of misfolded α-syn [5]. A reduction in proteasome activity appears to be linked to the accumulation of misfolded and aggregated α-syn [6] and genetic mutations in UPS components have been associated with neurodegeneration in familial forms of PD [7]. Responsible for PLOS ONE | DOI:10.1371/journal.pone.0120819 March 19, 2015
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