TFEB-Induced Autophagy to Increase Clearance of α-synuclein
Transcription factor EB (TFEB) is a regulator of autophagy, one of the processes by which cells clear out unwanted junk and damaged components. Enhancing autophagy via TFEB for therapeutic ends has been explored in a very preliminary fashion to date, such as in the context of treating atherosclerosis. Continuing in this vein, researchers here show that manipulating TFEB can increase clearance of the α-synuclein aggregates whose increased presence is associated with the age-related diseases collectively known as synucleinopathies:
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.Novel insights into the mechanisms of autophagy regulation have emerged with the recent discovery that the transcription factor EB (TFEB) controls the coordinated activation of the CLEAR (Coordinated Lysosomal Expression and Regulation) network. TFEB regulates lysosome biogenesis as well as autophagosome formation and autophagosome-lysosome fusion, thereby promoting cellular clearance. Based on this evidence we hypothesized that TFEB activation could prevent accumulation of α-syn aggregates by enhancing autophagic clearance.
We tested this hypothesis by using a human neuroglioma stable cell line that accumulates aggregated α-syn and demonstrated that overexpression of TFEB reduces the accumulation of aggregated α-syn. Specifically, we provide evidence that the reduced accumulation of α-syn aggregates correlates with TFEB activation and with upregulation of the CLEAR network and the autophagy system. We also show that chemical activation of TFEB using 2-hydroxypropyl-β-cyclodextrin (HPβCD) mediates autophagic clearance of aggregated α-syn. These results support the role of TFEB as a therapeutic target for the treatment of PD and potentially other neurodegenerative diseases characterized by protein aggregation.