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 - Funding Information:
We are thankful for the intellectual discussions and inputs from Dr. Ofer Yizhar, Professor Gil Levkowitz, Dr. Yaniv Ziv, Dr. Matthias Prigge, and Professor Brendan Lee. We acknowledge and thank the Weizmann Institute for providing financial and infrastructural support. We greatly appreciate the support provided by the lab of Professor Alon Chen (Weizmann Institute Israel and Max Planck Institute of Psychiatry in Munich). We are thankful for the technical assistance we received from Dr. Ron Rotkop, Dr. Ayala Sharp, Dr. Edna Peleg, Ms. Sivan Galai, and Mr. Sharon Ovadia from the Weizmann Institute and Dr. Rotem Engelman from the lab of Professor Moran Benhar from the Technion. A.E. is incumbent of the Leah Omenn Career Development Chair and is supported by research grants from the European research program (ERC614204) and the Israel Science Foundation (ISF) (1343/13; 1952/13). A.E. received additional support from the Adelis Foundation, the Henry S. and Anne S. Reich Research Fund, the Dukler Fund for Cancer Research, the Paul Sparr Foundation, the Saul and Theresa Esman Foundation, Joseph Piko Baruch, and from the estate of Fannie Sherr. Y. Kuperman. is the incumbent of the Sarah and Rolando Uziel Research Associate Chair. M.T. is the incumbent of the Carolito Stiftung Research Fellow Chair in Neurodegenerative Diseases. The behavioral human data presented in the work were collected by the Urea Cycle Disorders Consortium (UCDC) (U54HD061221), a part of the NIH Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research (ORDR), the National Center for Advancing Translational Science (NCATS), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The Urea Cycle Disorders Consortium is also supported by the O'Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. S.L. performed most of the experiments described in the manuscript; E.A. T.M. and A.B. measured the catecholamine contents; S.V. from M.S. lab performed the neuron firing analysis; R.E. helped with the immunostaining; Y. Kuperman, Y. Kuznetsov, and M.T. helped with the in vivo studies; R. Mazkereth helped with characterizing the phenotypes; R. McCarter from the UCDC performed the statistical analysis of the human data; S.C.S.N. provided us with the clinical data and analysis of ASLD patients as well as with crucial help with the writing of the manuscript; and M.S. and A.C. were highly involved in planning the relevant experiments and in the writing of the manuscript. A.E. initiated and led the study and wrote the manuscript. All authors were involved in discussions about study design and reviewed the manuscript. The authors declare no competing interests.
Funding Information:
We are thankful for the intellectual discussions and inputs from Dr. Ofer Yizhar, Professor Gil Levkowitz, Dr. Yaniv Ziv, Dr. Matthias Prigge, and Professor Brendan Lee. We acknowledge and thank the Weizmann Institute for providing financial and infrastructural support. We greatly appreciate the support provided by the lab of Professor Alon Chen ( Weizmann Institute Israel and Max Planck Institute of Psychiatry in Munich ). We are thankful for the technical assistance we received from Dr. Ron Rotkop, Dr. Ayala Sharp, Dr. Edna Peleg, Ms. Sivan Galai, and Mr. Sharon Ovadia from the Weizmann Institute and Dr. Rotem Engelman from the lab of Professor Moran Benhar from the Technion. A.E. is incumbent of the Leah Omenn Career Development Chair and is supported by research grants from the European research program ( ERC614204 ) and the Israel Science Foundation (ISF) ( 1343/13 ; 1952/13 ). A.E. received additional support from the Adelis Foundation , the Henry S. and Anne S. Reich Research Fund , the Dukler Fund for Cancer Research , the Paul Sparr Foundation , the Saul and Theresa Esman Foundation , Joseph Piko Baruch , and from the estate of Fannie Sherr . Y. Kuperman. is the incumbent of the Sarah and Rolando Uziel Research Associate Chair. M.T. is the incumbent of the Carolito Stiftung Research Fellow Chair in Neurodegenerative Diseases. The behavioral human data presented in the work were collected by the Urea Cycle Disorders Consortium (UCDC) ( U54HD061221 ), a part of the NIH Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research (ORDR), the National Center for Advancing Translational Science (NCATS), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The Urea Cycle Disorders Consortium is also supported by the O’Malley Foundation , the Rotenberg Family Fund , the Dietmar-Hopp Foundation , the Kettering Fund , and the National Urea Cycle Disorders Foundation .
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
UR - http://www.scopus.com/inward/record.url?scp=85075005345&partnerID=8YFLogxK
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
VL - 29
SP - 2144-2153.e7
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 8
ER -