Affiliations: [a]
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
| [b]
Department of Neurology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, Sichuan, China
| [c]
Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China
Correspondence:
[*]
Correspondence to: Guo-Jun Chen, 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, 1 Youyi Road, Chongqing 400016, China. Tel./Fax: +86 23 6870 8697; E-mail: [email protected].
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.
Keywords: Alzheimer’s disease, ANKRD24, autophagy, HMGCS2, ketone body, Tau
