skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal

Abstract

4-Hydroxy-2-nonenal (4HNE) and acrolein (ACR) are highly reactive neurotoxic products of lipid peroxidation that are implicated in the pathogenesis and progression of Alzheimer's and Parkinson's diseases. Conjugation with glutathione (GSH) initiates the 4HNE and ACR detoxification pathway, which generates the mercapturates of 4HNE and ACR that can be excreted. Prior work has shown that the efficiency of the GSH-dependent renal detoxification of haloalkene derived mercapturates is significantly decreased upon their deacetylation because of rapid transformation of the deacetylated products into toxic compounds mediated by β-lyase. The enzymes of the GSH-conjugation pathway and β-lyases are expressed in the brain, and we hypothesized that a similar toxicity mechanism may be initiated in the brain by the deacetylation of 4HNE- and ACR-mercapturate. The present study was performed to identify an enzyme(s) involved in 4HNE- and ACR-mercapturate deacetylation, characterize the brain expression of this enzyme and determine whether its inhibition decreases 4HNE and 4HNE-mercapturate neurotoxicity. We demonstrated that of two candidate deacetylases, aminoacylases 1 (AA1) and 3 (AA3), only AA3 efficiently deacetylates both 4HNE- and ACR-mercapturate. AA3 was further localized to neurons and blood vessels. Using a small molecule screen we generated high-affinity AA3 inhibitors. Two of them completely protected rat brain cortex neuronsmore » expressing AA3 from the toxicity of 4HNE-mercapturate. 4HNE-cysteine (4HNE-Cys) was also neurotoxic and its toxicity was mostly prevented by a β-lyase inhibitor, aminooxyacetate. The results suggest that the AA3 mediated deacetylation of 4HNE-mercapturate may be involved in the neurotoxicity of 4HNE.« less

Authors:
;  [1];  [2];  [3];  [4]; ;  [5];  [1]
  1. Department of Medicine, University of California at Los Angeles, CA 90095 (United States)
  2. Department of Neurology, University of California at Los Angeles, CA 90095 (United States)
  3. Brain Research Institute, University of California at Los Angeles, CA 90095 (United States)
  4. Institute of Genomics and Proteomics, University of California at Los Angeles, CA 90095 (United States)
  5. California NanoSystems Institute, University of California at Los Angeles, CA 90095 (United States)
Publication Date:
OSTI Identifier:
22215908
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 263; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACROLEIN; BLOOD VESSELS; BRAIN; CYSTEINE; DETOXIFICATION; GLUTATHIONE; INHIBITION; KIDNEYS; LIPIDS; LYASES; NERVE CELLS; NERVOUS SYSTEM DISEASES; PATHOGENESIS; RATS; TOXICITY

Citation Formats

Tsirulnikov, Kirill, Abuladze, Natalia, Bragin, Anatol, Brain Research Institute, University of California at Los Angeles, CA 90095, Faull, Kym, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, CA 90095, Pasarow Mass Spectrometry Laboratory, University of California at Los Angeles, CA 90095, Cascio, Duilio, Damoiseaux, Robert, Schibler, Matthew J., and Pushkin, Alexander. Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.07.002.
Tsirulnikov, Kirill, Abuladze, Natalia, Bragin, Anatol, Brain Research Institute, University of California at Los Angeles, CA 90095, Faull, Kym, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, CA 90095, Pasarow Mass Spectrometry Laboratory, University of California at Los Angeles, CA 90095, Cascio, Duilio, Damoiseaux, Robert, Schibler, Matthew J., & Pushkin, Alexander. Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal. United States. https://doi.org/10.1016/J.TAAP.2012.07.002
Tsirulnikov, Kirill, Abuladze, Natalia, Bragin, Anatol, Brain Research Institute, University of California at Los Angeles, CA 90095, Faull, Kym, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, CA 90095, Pasarow Mass Spectrometry Laboratory, University of California at Los Angeles, CA 90095, Cascio, Duilio, Damoiseaux, Robert, Schibler, Matthew J., and Pushkin, Alexander. 2012. "Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal". United States. https://doi.org/10.1016/J.TAAP.2012.07.002.
@article{osti_22215908,
title = {Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal},
author = {Tsirulnikov, Kirill and Abuladze, Natalia and Bragin, Anatol and Brain Research Institute, University of California at Los Angeles, CA 90095 and Faull, Kym and Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, CA 90095 and Pasarow Mass Spectrometry Laboratory, University of California at Los Angeles, CA 90095 and Cascio, Duilio and Damoiseaux, Robert and Schibler, Matthew J. and Pushkin, Alexander},
abstractNote = {4-Hydroxy-2-nonenal (4HNE) and acrolein (ACR) are highly reactive neurotoxic products of lipid peroxidation that are implicated in the pathogenesis and progression of Alzheimer's and Parkinson's diseases. Conjugation with glutathione (GSH) initiates the 4HNE and ACR detoxification pathway, which generates the mercapturates of 4HNE and ACR that can be excreted. Prior work has shown that the efficiency of the GSH-dependent renal detoxification of haloalkene derived mercapturates is significantly decreased upon their deacetylation because of rapid transformation of the deacetylated products into toxic compounds mediated by β-lyase. The enzymes of the GSH-conjugation pathway and β-lyases are expressed in the brain, and we hypothesized that a similar toxicity mechanism may be initiated in the brain by the deacetylation of 4HNE- and ACR-mercapturate. The present study was performed to identify an enzyme(s) involved in 4HNE- and ACR-mercapturate deacetylation, characterize the brain expression of this enzyme and determine whether its inhibition decreases 4HNE and 4HNE-mercapturate neurotoxicity. We demonstrated that of two candidate deacetylases, aminoacylases 1 (AA1) and 3 (AA3), only AA3 efficiently deacetylates both 4HNE- and ACR-mercapturate. AA3 was further localized to neurons and blood vessels. Using a small molecule screen we generated high-affinity AA3 inhibitors. Two of them completely protected rat brain cortex neurons expressing AA3 from the toxicity of 4HNE-mercapturate. 4HNE-cysteine (4HNE-Cys) was also neurotoxic and its toxicity was mostly prevented by a β-lyase inhibitor, aminooxyacetate. The results suggest that the AA3 mediated deacetylation of 4HNE-mercapturate may be involved in the neurotoxicity of 4HNE.},
doi = {10.1016/J.TAAP.2012.07.002},
url = {https://www.osti.gov/biblio/22215908}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 263,
place = {United States},
year = {Sat Sep 15 00:00:00 EDT 2012},
month = {Sat Sep 15 00:00:00 EDT 2012}
}