title: NPAS4 Facilitates the Autophagic Clearance of Endogenous Tau in Rat Cortical Neurons.
abstract: Tau, a microtubule-binding phosphoprotein, plays a critical role in the stabilisation of microtubules and neuronal function. However, hyperphosphorylated tau is involved in the pathogenesis of Alzheimer's disease (AD) and other tauopathies. The facilitation of tau clearance is now regarded as a valid therapeutic strategy for these neurodegenerative tauopathies. Here, we provide the first demonstration that the over-expression of neuronal PAS domain protein 4 (NPAS4)-induced autophagy and effectively facilitated the clearance of endogenous total and phosphorylated tau in rat primary cortical neurons. Moreover, the activation of autophagy by serum depletion significantly decreased endogenous total and phosphorylated tau levels. Autophagy inhibitors, such as 3-methyladenine (3-MA) and chloroquine (CQ), induced tau aggregation. However, NPAS4 over-expression reversed the aggregation of tau that was induced by the inhibition of autophagy. Interestingly, proteasome inhibition by MG132, had no effect on autophagy, but did reduce tau levels, indicating that NPAS4 may also degrade tau proteins through an unknown proteasome-mediated mechanism. Furthermore, NPAS4 did not alter the activity of two major tau kinases, glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5). Taken together, the results indicate that targeting NPAS4 could provide a therapeutic approach for the treatment of AD and other tauopathies.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China.|Department of Neurology, The Ninth People's Hospital of Chongqing, 69 Jialing Road, Chongqing, 400700, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Fan
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China. woodchen2015@163.com.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China. zhubinglin0311@163.com.
authors.forename: Binglin
authors.initials: B
authors.lastname: Zhu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000225:Adenine; D051792:Basic Helix-Loop-Helix Proteins; D002738:Chloroquine; D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; D007976:Leupeptins; D016875:tau Proteins; C516513:Npas4 protein, rat; C025946:3-methyladenine; C495907:Cdk5 protein, rat; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Autophagy; Cortical neurons; NPAS4; Tau; Tauopathies