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ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus

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Anderzhanova,  Elmira
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Chen,  Alon
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Lerner, S., Anderzhanova, E., Verbitsky, S., Eilam, R., Kuperman, Y., Tsoory, M., et al. (2019). ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus. CELL REPORTS, 29(8), 2144-2153. doi:10.1016/j.celrep.2019.10.043.


Cite as: https://hdl.handle.net/21.11116/0000-0009-5CDC-9
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.