Affiliations: [a] Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ, USA | [b] Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA, USA | [c] Institute of Bioorganic Chemistry, Poznań, Poland | [d] Department of Biochemistry and Biotechnology, University of Life Sciences, Poznań, Poland | [e] Permanent Affiliation: Department of Environmental Chemistry, Łódź University, Łódź, Poland
Correspondence:
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Correspondence to: Hieronim Jakubowski, Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren Street Newark, NJ 07101-1709, USA. Tel.: +1 973 972 4483; Ext.: 28733; Fax: +1 973 972 8981; E-mail: [email protected].
Abstract: Homocysteine (Hcy)-thiolactone is toxic, induces epileptic seizures in rodents, and has been implicated in Alzheimer's disease. Paraoxonase 1 (Pon1), a component of high-density lipoprotein, hydrolyzes Hcy-thiolactone in vitro. Whether this reflects a physiological function and whether Pon1 can protect against Hcy-thiolactone toxicity was unknown. Here we show that Hcy-thiolactone was elevated in brains of Pon1−/− mice (1.5-fold, p = 0.047) and that Pon1−/− mice excrete more Hcy-thiolactone than wild type animals (2.4-fold, p = 0.047). The frequency of seizures induced by intraperitoneal injections of L-Hcy-thiolactone was significantly higher in Pon1−/− mice compared with wild type animals (52.8% versus 29.5%, p = 0.042); the latency of seizures was lower in Pon1−/− mice than in wild type animals (31.8 min versus 41.2 min, p = 0.019). Using the Pon1 null mice, we provide the first direct evidence that a specific Hcy metabolite, Hcy-thiolactone, rather than Hcy itself is neurotoxic in vivo. Our findings indicate that Pon1 protects mice against Hcy-thiolactone neurotoxicity by hydrolyzing it in the brain, and suggest a mechanism by which Pon1 can protect against neurodegeneration associated with hyperhomocysteinemia and Alzheimer's disease.
