HMGCS2 promotes autophagic degradation of the amyloid-β precursor protein through ketone body-mediated mechanisms

Li Tian Hu, Bing Lin Zhu, Yu Jie Lai, Yan Long, Jing Si Zha, Xiao Tong Hu, John H. Zhang, Guo Jun Chen

Research output: Contribution to journalArticlepeer-review

Abstract

HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) is a control enzyme in ketogenesis. The mitochondrial localization and interaction with APP (β-amyloid precursor protein) suggest that HMGCS2 may play a role in the pathophysiology of AD (Alzheimer's disease). Here we report that overexpression of HMGCS2 decreased levels of APP and related CTFs (carboxy-terminal fragments), which was largely prevented by an autophagic inhibitor chloroquine. In addition, HMGCS2 enhancement of autophagic marker LC3II was diminished by rapamycin, an inhibitor of mechanistic target of rapamycin. Moreover, deprivation of EBSS (Earle's Balanced Salt Solution) significantly augmented the effect of HMGCS2 on LC3II, while acetoacetate reversed the reduction of LC3II, APP and CTFs which was induced by HMGCS2 knockdown. In the presence of acetoacetate, rapamycin failed to induce further increase of LC3II, which mimicked the effect of HMGCS2 overexpression. Finally, HMGCS2 enhanced the antioxidant response. Collectively, HMGCS2 shares with ketone bodies common features in autophagic clearance of APP and CTFs, suggesting that ketone bodies play an important role in HMGCS2 regulation of the autophagy.

Original languageEnglish
Pages (from-to)492-498
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume486
Issue number2
DOIs
StatePublished - Apr 29 2017

ASJC Scopus Subject Areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Keywords

  • Alzheimer's disease
  • Autophagy
  • HMGCS2
  • Ketone bodies
  • β-amyloid precursor protein
  • Amyloid beta-Protein Precursor/metabolism
  • Hippocampus/cytology
  • Humans
  • RNA, Small Interfering/genetics
  • Microtubule-Associated Proteins/genetics
  • Sirolimus/pharmacology
  • Autophagy/genetics
  • HEK293 Cells
  • Transgenes
  • Cell Line
  • Hydroxymethylglutaryl-CoA Synthase/antagonists & inhibitors
  • Signal Transduction
  • Recombinant Proteins/genetics
  • Gene Expression Regulation
  • Neurons/cytology
  • Chloroquine/pharmacology
  • Acetoacetates/pharmacology
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • Animals
  • Ketone Bodies/metabolism
  • Mice
  • Proteolysis/drug effects

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