ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus
Shaul Lerner, Elmira Anderzhanova, Sima Verbitsky, Raya Eilam, Yael Kuperman, Michael Tsoory, Yuri Kuznetsov, Alexander Brandis, Tevie Mehlman, Ram Mazkereth, UCDC Neuropsychologists, Robert McCarter, Menahem Segal, Sandesh C S Nagamani, Alon Chen, Ayelet Erez, Fabienne Dietrich Alber, Talin Babikian, Heidi Bender, Christopher Boys, David Breiger, Corinna Buerger, Peter Burgard, Mina Nguyen-Driver, Benjamin Goodlett, Elizabeth Kerr, Casey Krueger, Eva Mamak, Jacqueline H Sanz, David Schwartz, Susan Caudle, Arianna Stefanos, Rachel Tangen, Magdalena Walter, Susan Waisbren, Greta Wilkening, Shaul Lerner, Elmira Anderzhanova, Sima Verbitsky, Raya Eilam, Yael Kuperman, Michael Tsoory, Yuri Kuznetsov, Alexander Brandis, Tevie Mehlman, Ram Mazkereth, UCDC Neuropsychologists, Robert McCarter, Menahem Segal, Sandesh C S Nagamani, Alon Chen, Ayelet Erez, Fabienne Dietrich Alber, Talin Babikian, Heidi Bender, Christopher Boys, David Breiger, Corinna Buerger, Peter Burgard, Mina Nguyen-Driver, Benjamin Goodlett, Elizabeth Kerr, Casey Krueger, Eva Mamak, Jacqueline H Sanz, David Schwartz, Susan Caudle, Arianna Stefanos, Rachel Tangen, Magdalena Walter, Susan Waisbren, Greta Wilkening
Abstract
Patients with germline mutations in the urea-cycle enzyme argininosuccinate lyase (ASL) are at risk for developing neurobehavioral and cognitive deficits. We find that ASL is prominently expressed in the nucleus locus coeruleus (LC), the central source of norepinephrine. Using natural history data, we show that individuals with ASL deficiency are at risk for developing attention deficits. By generating LC-ASL-conditional knockout (cKO) mice, we further demonstrate altered response to stressful stimuli with increased seizure reactivity in LC-ASL-cKO mice. Depletion of ASL in LC neurons leads to reduced amount and activity of tyrosine hydroxylase (TH) and to decreased catecholamines synthesis, due to decreased nitric oxide (NO) signaling. NO donors normalize catecholamine levels in the LC, seizure sensitivity, and the stress response in LC-ASL-cKO mice. Our data emphasize ASL importance for the metabolic regulation of LC function with translational relevance for ASL deficiency (ASLD) patients as well as for LC-related pathologies.
Keywords: ASL; locus coeruleus; nitric oxide; stress response; tyrosine hydroxylase; urea cycle disorders.
Conflict of interest statement
The authors declare no competing interests.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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References
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