Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer

Nature Communications
Julien BaruteauSimon N Waddington

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. Intravenous injection of AAV8 vector into adult or neonatal ASL-deficient mice demonstrates long-term correction of the hepatic urea cycle and the cerebral citrulline-NO cycle, respectively. Cerebral disease persists if ammonaemia only is normalised but is dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This correlates with behavioural improvement and reduced cortical cell death. Thus, neuronal oxidative/nitrosative stress is a distinct pathophysiological mechanism from hyperammonaemia. Disease amelioration by simultaneous brain and liver gene transfer with one vector, to treat both metabolic pathways, provides new hope for hepatocerebral metabolic diseases.

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Citations

Feb 7, 2019·Journal of Inherited Metabolic Disease·Julien BaruteauJohannes Häberle
Jun 23, 2019·Human Molecular Genetics·Leandro R SoriaNicola Brunetti-Pierri
Jan 17, 2020·Human Mutation·Matthias ZielonkaUNKNOWN Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD
May 22, 2019·Journal of Human Genetics·Shirou MatsumotoKimitoshi Nakamura
Dec 29, 2020·EMBO Molecular Medicine·Leandro R SoriaNicola Brunetti-Pierri
May 4, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Matthew NitzahnGerald S Lipshutz
Feb 22, 2021·Journal of Cellular and Molecular Medicine·Fang LiuShao-Guang Lv
Dec 16, 2020·Molecular Genetics and Metabolism·Matthew Nitzahn, Gerald S Lipshutz

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Methods Mentioned

BETA
ELISA
PCR
transgenic
transfection
electrophoresis
Fluorescence
protein assay

Clinical Trials Mentioned

NCT03064048

Software Mentioned

JACoP
Primeview
Matlab
Image Analysis
StepOne TM
Leica Application Suite Advanced Fluorescence
Pro Premier
MouseLabTracker
mAsl
ImageJ

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