Asl, short for argininosuccinate lyase, is an enzyme-encoding gene. It plays a crucial role in the urea cycle, where it cleaves argininosuccinic acid into arginine and fumarate. This function is vital for nitrogen metabolism and maintaining normal ammonia levels in the body [1].

Patients with germline mutations in Asl are at risk of developing neurobehavioral and cognitive deficits. By generating LC-Asl-conditional knockout (CKO) mice, it was demonstrated that depletion of Asl in LC neurons leads to reduced amount and activity of tyrosine hydroxylase (TH), decreased catecholamines synthesis due to decreased nitric oxide (NO) signaling. These mice also showed an altered response to stressful stimuli with increased seizure reactivity. NO donors normalized catecholamine levels, seizure sensitivity, and the stress response in these CKO mice, emphasizing Asl's importance for the metabolic regulation of LC function [2].

In conclusion, Asl is essential for the urea cycle and ammonia regulation. The use of Asl CKO mouse models has revealed its role in the metabolic regulation of the nucleus locus coeruleus function, which is relevant to understanding the pathophysiology of Asl deficiency-related neurobehavioral and cognitive deficits.

References:

1. Balmer, Cécile, Pandey, Amit V, Rüfenacht, Véronique, Wong, Lee-Jun, Häberle, Johannes. 2013. Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene. In Human mutation, 35, 27-35. doi:10.1002/humu.22469. https://pubmed.ncbi.nlm.nih.gov/24166829/

2. Lerner, Shaul, Anderzhanova, Elmira, Verbitsky, Sima, Chen, Alon, Erez, Ayelet. . ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus. In Cell reports, 29, 2144-2153.e7. doi:10.1016/j.celrep.2019.10.043. https://pubmed.ncbi.nlm.nih.gov/31747589/