TY - JOUR
T1 - ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus
AU - UCDC Neuropsychologists
AU - Lerner, Shaul
AU - Anderzhanova, Elmira
AU - Verbitsky, Sima
AU - Eilam, Raya
AU - Kuperman, Yael
AU - Tsoory, Michael
AU - Kuznetsov, Yuri
AU - Brandis, Alexander
AU - Mehlman, Tevie
AU - Mazkereth, Ram
AU - Alber, Fabienne Dietrich
AU - Babikian, Talin
AU - Bender, Heidi
AU - Boys, Christopher
AU - Breiger, David
AU - Buerger, Corinna
AU - Burgard, Peter
AU - Nguyen-Driver, Mina
AU - Goodlett, Benjamin
AU - Kerr, Elizabeth
AU - Krueger, Casey
AU - Mamak, Eva
AU - Sanz, Jacqueline H.
AU - Schwartz, David
AU - Caudle, Susan
AU - Stefanos, Arianna
AU - Tangen, Rachel
AU - Walter, Magdalena
AU - Waisbren, Susan
AU - Wilkening, Greta
AU - McCarter, Robert
AU - Segal, Menahem
AU - Nagamani, Sandesh C.S.
AU - Chen, Alon
AU - Erez, Ayelet
N1 - Publisher Copyright:
© 2019 The Author(s)
PY - 2019/11/19
Y1 - 2019/11/19
N2 - 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.
AB - 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.
KW - ASL
KW - locus coeruleus
KW - nitric oxide
KW - stress response
KW - tyrosine hydroxylase
KW - urea cycle disorders
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UR - http://www.scopus.com/inward/citedby.url?scp=85075005345&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.10.043
DO - 10.1016/j.celrep.2019.10.043
M3 - Article
C2 - 31747589
AN - SCOPUS:85075005345
SN - 2211-1247
VL - 29
SP - 2144-2153.e7
JO - Cell Reports
JF - Cell Reports
IS - 8
ER -