ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus

• DOI: 10.1016/j.celrep.2019.10.043
• Publication Date: 2019-11-19T15:44:26Z
• Authors: Shaul Lerner; Elmira Anderzhanova; Sima Verbitsky; Raya Eilam; Yael Kuperman; Michael Tsoory; Yuri Kuznetsov; Alexander Brandis; Tevie Mehlman; Ram Mazkereth; Robert McCarter; Menahem Segal; Sandesh C.S. Naga...; Alon Chen; Ayelet Erez; Fabienne Dietrich...; 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
• Keywords: Locus coeruleus; Argininosuccinate synthase; Argininosuccinate lyase; Conditional gene knockout

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 nucleus locus coeruleus (LC), central source of norepinephrine. Using natural history data, we show individuals deficiency attention By generating LC-ASL-conditional knockout (cKO) mice, further demonstrate altered response to stressful stimuli increased seizure reactivity LC-ASL-cKO mice. Depletion LC neurons leads reduced amount activity tyrosine hydroxylase (TH) decreased catecholamines synthesis, due nitric oxide (NO) signaling. NO donors normalize catecholamine levels LC, sensitivity, stress Our data emphasize importance metabolic regulation function translational relevance (ASLD) patients as well LC-related pathologies.