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  ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-FA92-C Version Permalink: http://hdl.handle.net/21.11116/0000-0005-FA93-B
Genre: Journal Article

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 Creators:
Lerner, Shaul, Author
Anderzhanova, Elmira1, 2, Author              
Verbitsky, Sima, Author
Eilam, Raya, Author
Kuperman, Yael, Author
Tsoory, Michael, Author
Kuznetsov, Yuri, Author
Brandis, Alexander, Author
Mehlman, Tevie, Author
Mazkereth, Ram, Author
McCarter, Robert, Author
Segal, Menahem, Author
Nagamani, Sandesh C. S., Author
Chen, Alon1, Author              
Erez, Ayelet, Author
Affiliations:
1Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035294              
2AG Wotjak, Carsten, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society, ou_1607166              

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 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.

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Language(s): eng - English
 Dates: 2019-11-19
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
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Title: Cell Reports
Source Genre: Journal
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Publ. Info: Maryland Heights, MO : Cell Press
Pages: - Volume / Issue: 29 (8) Sequence Number: - Start / End Page: 2144 - 2153 Identifier: ISSN: 2211-1247
CoNE: https://pure.mpg.de/cone/journals/resource/2211-1247