Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB

EMBO Molecular Medicine - Tập 6 Số 9 - Trang 1142-1160 - 2014
Vinicia Assunta Polito1, Hongmei Li1, Heidi Martini‐Stoica1,2,3, Baiping Wang4,1, Yang Li1, Yin Xu1, Daniel B. Swartzlander1, Michela Palmieri5,4, Alberto di Ronza5,4, Virginia M.‐Y. Lee6, Marco Sardiello5,4, Andrea Ballabio5,4,7, Hui Zheng4,1,3
1Huffington Center on Aging Baylor College of Medicine Houston TX USA
2Interdepartmental Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
3Medical Scientist Training Program Baylor College of Medicine Houston TX USA
4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;
5Dan and Jan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
6Department of Pathology and Lab Medicine University of Pennsylvania School of Medicine Philadelphia PA USA
7Department of Translational Medical Sciences Section of Pediatrics Telethon Institute of Genetics and Medicine Federico II University Naples Italy

Tóm tắt

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.

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Tài liệu tham khảo

10.1093/nar/gks1193

10.1038/nrd2959

10.1111/acel.12057

10.1046/j.1365-2818.1999.00460.x

10.1126/science.1208607

10.1073/pnas.1305623110

10.1172/JCI29715

10.1073/pnas.0709180105

Franklin KBJ, 2001, The Mouse Brain in Stereotaxic Coordinates

10.1186/1750-1326-4-13

10.1212/01.WNL.0000063311.58879.01

10.1200/JCO.2010.32.6223

10.1016/j.neuron.2006.09.016

10.1038/nrneurol.2011.200

10.1038/nprot.2008.211

10.1186/1750-1326-7-48

10.1016/j.febslet.2006.04.064

10.4161/auto.4451

10.2478/s13380-012-0032-y

10.1016/j.neurobiolaging.2011.11.009

10.1016/j.neuron.2006.03.023

10.1073/pnas.2132711100

10.1038/ng781

10.1023/B:NEUR.0000021904.61387.95

10.1093/bioinformatics/btq430

10.1101/cshperspect.a006247

10.1016/j.devcel.2011.07.016

10.1016/j.neuron.2006.07.027

10.1038/nrd3842

10.1242/jcs.019265

10.1093/jnen/64.2.113

10.1016/j.nbd.2011.01.021

10.1523/JNEUROSCI.1202-06.2006

10.1371/journal.pone.0062459

10.1093/hmg/ddr306

10.1523/JNEUROSCI.1964-10.2010

Pickford F, 2008, The autophagy‐related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice, J Clin Invest, 118, 2190

10.1523/JNEUROSCI.3279-05.2005

10.1126/scisignal.2002790

10.1016/j.nbd.2010.11.003

10.1126/science.1113694

10.1126/science.1174447

10.1093/brain/aws143

10.1038/nmeth.2019

10.1126/science.1204592

10.1038/emboj.2012.32

10.1038/nrm3330

10.1093/hmg/ddt052

10.1113/jphysiol.2011.220236

10.1073/pnas.0506580102

10.1073/pnas.1222803110

10.1093/hmg/ddm364

10.1093/nar/gks1050

10.1016/j.cell.2006.11.039

10.1093/hmg/ddp367

10.4161/auto.6.1.10815

10.1002/cne.902960102

10.1093/brain/awq341

10.1096/fj.06-5721fje

10.1186/1750-1326-1-7

10.1523/JNEUROSCI.5685-08.2009

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EMBO Molecular Medicine

Tập 6 Số 9

1142-1160

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