HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24

Author:

Hu Li-Tian12,Xie Xiao-Yong1,Zhou Gui-Feng1,Wen Qi-Xin1,Song Li1,Luo Biao1,Deng Xiao-Juan1,Pan Qiu-Ling1,Chen Guo-Jun13

Affiliation:

1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Key Laboratory of Neurology, Chongqing, China

2. Department of Neurology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, Sichuan, China

3. Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China

Abstract

Background: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer’s disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. Objective: The present study was to investigate the role of HMGCS2 in Tau/p degradation. Methods: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. Results: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. Conclusion: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

Publisher

IOS Press

Subject

Psychiatry and Mental health,Geriatrics and Gerontology,Clinical Psychology,General Medicine,General Neuroscience

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