ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus

UCDC Neuropsychologists

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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. Lerner et al. show that ASL is expressed greatly in the nucleus locus coeruleus (LC), where it regulates NO levels. ASL deficiency in the LC of mice results in abnormal response to stress and in increased seizure sensitivity due to decreased TH activity and catecholamine synthesis. NO donors rescue the phenotype in LC-ASL-deficient mice.

Original languageEnglish (US)
Pages (from-to)2144-2153.e7
JournalCell Reports
Volume29
Issue number8
DOIs
StatePublished - Nov 19 2019

Keywords

  • ASL
  • locus coeruleus
  • nitric oxide
  • stress response
  • tyrosine hydroxylase
  • urea cycle disorders

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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