期刊
CELL REPORTS
卷 29, 期 8, 页码 2144-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.10.043
关键词
-
类别
资金
- Weizmann Institute
- European research program [ERC614204]
- Israel Science Foundation (ISF) [1343/13, 1952/13]
- Adelis Foundation
- Henry S. and Anne S. Reich Research Fund
- Dukler Fund for Cancer Research
- Paul Sparr Foundation
- Saul and Theresa Esman Foundation
- Joseph Piko Baruch
- estate of Fannie Sherr
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据