title: Genetic and chemical activation of TFEB mediates clearance of aggregated α-synuclein.
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.
authors: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas, United States of America.
authors: Kiri
authors: K
authors: Kilpatrick
authors: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas, United States of America.
authors: Yimeng
authors: Y
authors: Zeng
authors: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas, United States of America.
authors: Tommy
authors: T
authors: Hancock
authors: 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.
authors: Laura
authors: L
authors: Segatori
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D066329:Protein Aggregates; D034741:RNA, Small Interfering; C064972:TFEB protein, human; D051844:alpha-Synuclein; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin