Simvastatin inhibits protein isoprenylation in the brain

• Type of Material: Article
• Authors: Stephen M. Ostrowski, Case Western Reserve University; Kachael Johnson, Emory University; Matthew Siefert, Cincinnati Children's Hospital Medical Center; Sam Shank, Case Western Reserve University; Luigi Sironi, University of Milan; Benjamin Wolozin, Boston University; Gary E. Landreth, Case Western Reserve University; Assem Ziady, Emory University
• Language: English
• Date: 2016-08-04
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 IBRO.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuroscience.2016.04.053
• Title of Journal or Parent Work: Neuroscience
• ISSN: 0306-4522
• Volume: 329
• Start Page: 264
• End Page: 274
• Grant/Funding Information: This work was supported by grants from the Alzheimer’s Association and the Blanchette Hooker Rockefeller Foundation to GL. SM was supported by the Case Medical Scientist Training Program Grant, T32 GM07250.; AZ was supported by the NHLBI (1R01HL109362-01 (Ziady)).
• Keywords: simvastatin; Life Sciences & Biomedicine; IN-VIVO; Alzheimer's disease; RISK-FACTOR; CONTROLLED-TRIAL; Rab; STATINS; GERANYLGERANYL PYROPHOSPHATE; Cdc42; RhoA; CARBOXYL METHYLTRANSFERASE; GTP-BINDING PROTEINS; TOTAL CHOLESTEROL; isoprenylation; Science & Technology; ALZHEIMER-DISEASE; Neurosciences & Neurology; Neurosciences; ISOPRENOID MODIFICATION
• Research Categories: Biology, Molecular; Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, may reduce the risk of Alzheimer's disease (AD). Statin action in patients with AD, as in those with heart disease, is likely to be at least partly independent of the effects of statins on cholesterol. Statins can alter cellular signaling and protein trafficking through inhibition of isoprenylation of Rho, Cdc42, and Rab family GTPases. The effects of statins on protein isoprenylation in vivo, particularly in the central nervous system, are poorly studied. We utilized two-dimensional gel electrophoresis approaches to directly monitor the levels of isoprenylated and non-isoprenylated forms of Rho and Rab family GTPases. We report that simvastatin significantly inhibits RhoA and Rab4, and Rab6 isoprenylation at doses as low as 50 nM in vitro. We also provide the first in vivo evidence that statins inhibit the isoprenylation of RhoA in the brains of rats and RhoA, Cdc42, and H-Ras in the brains of mice treated with clinically relevant doses of simvastatin.