title: Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB.
abstract: Accumulating evidence implicates impairment of the autophagy-lysosome pathway in Alzheimer's disease (AD). Recently discovered, transcription factor EB (TFEB) is a molecule shown to play central roles in cellular degradative processes. Here we investigate the role of TFEB in AD mouse models. In this study, we demonstrate that TFEB effectively reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the rTg4510 mouse model of tauopathy with no detectable adverse effects when expressed in wild-type mice. TFEB specifically targets hyperphosphorylated and misfolded Tau species present in both soluble and aggregated fractions while leaving normal Tau intact. We provide in vitro evidence that this effect requires lysosomal activity and we identify phosphatase and tensin homolog (PTEN) as a direct target of TFEB that is required for TFEB-dependent aberrant Tau clearance. The specificity and efficacy of TFEB in mediating the clearance of toxic Tau species makes it an attractive therapeutic target for treating diseases of tauopathy including AD.
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors: Vinicia A
authors: VA
authors: Polito
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors: Hongmei
authors: H
authors: Li
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA Interdepartmental Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
authors: Heidi
authors: H
authors: Martini-Stoica
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors: Baiping
authors: B
authors: Wang
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors: Li
authors: L
authors: Yang
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors: Yin
authors: Y
authors: Xu
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors: Daniel B
authors: DB
authors: Swartzlander
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Dan and Jan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: Michela
authors: M
authors: Palmieri
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Dan and Jan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: Alberto
authors: A
authors: di Ronza
authors: Department of Pathology and Lab Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Virginia M-Y
authors: VM
authors: Lee
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Dan and Jan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: Marco
authors: M
authors: Sardiello
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Dan and Jan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA Department of Translational Medical Sciences, Section of Pediatrics, Telethon Institute of Genetics and Medicine Federico II University, Naples, Italy.
authors: Andrea
authors: A
authors: Ballabio
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA huiz@bcm.edu.
authors: Hui
authors: H
authors: Zheng
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D024801:Tauopathies / Q000235:genetics* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C558298:Mapt protein, mouse; C484068:Tcfeb protein, mouse; D016875:tau Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Alzheimer's disease; PTEN; TFEB; autophagy‐lysosomal pathway; tauopathy