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

作者全名："Hu, Li-Tian; Xie, Xiao-Yong; Zhou, Gui-Feng; Wen, Qi-Xin; Song, Li; Luo, Biao; Deng, Xiao-Juan; Pan, Qiu-Ling; Chen, Guo-Jun"

作者地址："[Hu, Li-Tian; Xie, Xiao-Yong; Zhou, Gui-Feng; Wen, Qi-Xin; Song, Li; Luo, Biao; Deng, Xiao-Juan; Pan, Qiu-Ling; Chen, Guo-Jun] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol,Chongqing Key Lab Neurol, Chongqing Key Lab Major Neurol & Mental Disorders, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Hu, Li-Tian] North Sichuan Med Coll, Clin Coll 2, Nanchong Cent Hosp, Dept Neurol, Nanchong, Sichuan, Peoples R China; [Chen, Guo-Jun] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing, Peoples R China"

通信作者："Chen, GJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol,Chongqing Key Lab Neurol, Chongqing Key Lab Major Neurol & Mental Disorders, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF ALZHEIMERS DISEASE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000908400500028

JCR分区：Q2

影响因子：3.4

年份：2023

卷号：91

期号：1

开始页：407

结束页：426

文献类型：Article

关键词：Alzheimer's disease; ANKRD24; autophagy; HMGCS2; ketone body; Tau

摘要："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-beta 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 beta-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."

基金机构：NSFC [81971030]; Chongqing Education commission [KJZD-K201900404]; Strategic Science & Technology Cooperation Project of North Sichuan Medical College and Nanchong Municipal Government [18SXHZ0184]; Scientific Research Development Project of North Sichuan Medical College [CBY17-A-ZD03]; Sichuan Provincial Health and Family Planning Commission [18PJ335]

基金资助正文："This work was supported by NSFC (81971030) and Chongqing Education commission (KJZD-K201900404) to G-J Chen and by The Strategic Science & Technology Cooperation Project of North Sichuan Medical College and Nanchong Municipal Government (18SXHZ0184), Scientific Research Development Project of North Sichuan Medical College (CBY17-A-ZD03) and Sichuan Provincial Health and Family Planning Commission (18PJ335) to Li-Tian Hu.; Authors' disclosures available online (https://www.j-alz.com/manuscript-disclosures/22-0640r2)."