HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24.
J Alzheimers Dis
; 91(1): 407-426, 2023.
Article
em En
| MEDLINE
| ID: mdl-36442191
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-ß 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 ß-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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
/
Doença de Alzheimer
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article