2018
DOI: 10.1038/s41467-018-05972-1
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Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer

Abstract: Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and the citrulline-nitric oxide (NO) cycle producing NO. ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia, multiorgan disease and neurocognitive impairment despite treatment aiming to normalise ammonaemia without considering NO imbalance. Here we show that cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intrave… Show more

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Cited by 36 publications
(66 citation statements)
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“…To understand the roles of ASL in the brain, we first determined the distribution of ASL using in situ hybridization (ISH) and immunostaining in coronal sections of brain obtained from wild-type mice. Consistent with previous reports, we found sparse expression of ASL in different brain regions (Baruteau et al., 2018, Braissant, 2004); however, we found a prominent expression in the LC nuclei (Figures 1A and S1). In brainstem sections from mice as well as in brain tissue array from humans, we find ASL expression to distinctly co-localize with tyrosine hydroxylase (TH) expression, the gold standard for marking the LC region (Figures 1B and 1C).…”
Section: Resultssupporting
confidence: 92%
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“…To understand the roles of ASL in the brain, we first determined the distribution of ASL using in situ hybridization (ISH) and immunostaining in coronal sections of brain obtained from wild-type mice. Consistent with previous reports, we found sparse expression of ASL in different brain regions (Baruteau et al., 2018, Braissant, 2004); however, we found a prominent expression in the LC nuclei (Figures 1A and S1). In brainstem sections from mice as well as in brain tissue array from humans, we find ASL expression to distinctly co-localize with tyrosine hydroxylase (TH) expression, the gold standard for marking the LC region (Figures 1B and 1C).…”
Section: Resultssupporting
confidence: 92%
“…This is best illustrated by the complex phenotype observed in individuals with argininosuccinic aciduria or ASL deficiency (ASLD), a urea cycle disorder that is caused by germline, loss-of-function, pathogenic variants in ASL (Baruteau et al., 2017, Erez et al., 2011a, Mercimek-Mahmutoglu et al., 2010, Nagamani et al., 2011, Nagamani et al., 2012b, Tuchman et al., 2008). In spite of having fewer episodes of hyperammonemia as compared to individuals with other urea cycle disorders (UCDs), individuals with ASLD are at increased risk to develop intellectual and learning disabilities, behavioral abnormalities, epilepsy, ataxia, and hypertension (Baruteau et al., 2018, Brunetti-Pierri et al., 2009, Ficicioglu et al., 2009, Kho et al., 2018, Kleijer et al., 2002, Lågas and Ruokonen, 1991, Tuchman et al., 2000). Thus, pathogenic mechanisms other than hyperammonemia likely contribute to the phenotypes observed in ASLD.…”
Section: Introductionmentioning
confidence: 99%
“…As previously demonstrated, plasma ALT and AST were significantly elevated in Asl Neo/Neo mice as compared with WT littermates, whereas direct bilirubin and albumin were not significantly different ( Figure 3, A and B, Supplemental Figure 3, and refs. 2,26,27). In addition, the Asl Neo/Neo mice had hepatomegaly as compared with WT littermates ( Figure 3C).…”
Section: L I N I C a L M E D I C I N Ementioning
confidence: 92%
“…More studies are needed to investigate this hypothesis, especially since increases in hepatic glycogen are observed in several of the proximal disorders, including OTCD, which was associated with lower prevalence of chronic hepatocellular injury in the UCDC longitudinal study cohort (15,45). Interestingly, this hepatic glycogen accumulation as assessed by H&E staining in the murine model was previously rescued using an AAV8-mediated gene therapy with ubiquitous promoter (26). Similarly, we demonstrate rescue of both the hepatic glycogen accumulation and hepatic glycogen phosphorylase activity with helper-dependent adenovirus expressing Asl with a hepatocyte-specific promoter and enhancer, which suggests that the phenotype may be cell autonomous.…”
Section: L I N I C a L M E D I C I N Ementioning
confidence: 99%
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