HMGCS2 promotes autophagic degradation of the amyloid-β precursor protein through ketone body-mediated mechanisms.
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.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China; Department of Neurology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong 637000, Sichuan, China.
Li-Tian
LT
Hu
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
Bing-Lin
BL
Zhu
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
Yu-Jie
YJ
Lai
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
Yan
Y
Long
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
Jing-Si
JS
Zha
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
Xiao-Tong
XT
Hu
Division of Physiology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
John H
JH
Zhang
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China. Electronic address: woodchen2015@163.com.
Guo-Jun
GJ
Chen
D000090:Acetoacetates / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
D000090:Acetoacetates; D016564:Amyloid beta-Protein Precursor; C000599408:HMGCS2 protein, human; D007657:Ketone Bodies; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C016635:acetoacetic acid; D002738:Chloroquine; D006904:Hydroxymethylglutaryl-CoA Synthase; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
3-Methyladenine (PubChem CID:1673); Acetoacetate (PubChem CID:2724246); Alzheimer's disease; Autophagy; Chloroquine (PubChem CID:83818); HMGCS2; Ketone bodies; Rapamycin (PubChem CID:5284616); Vinblastine (PubChem CID:5388983); Wortmannin (PubChem CID:312145); hydrogen peroxide (PubChem CID:784); β-amyloid precursor protein