Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer

Julien Baruteau, Dany P Perocheau, Joanna Hanley, Maëlle Lorvellec, Eridan Rocha-Ferreira, Rajvinder Karda, Joanne Ng, Natalie Suff, Juan Antinao Diaz, Ahad A Rahim, Michael P Hughes, Blerida Banushi, Helen Prunty, Mariya Hristova, Deborah A Ridout, Alex Virasami, Simon Heales, Stewen J Howe, Suzanne M K Buckley, Philippa B MillsPaul Gissen, Simon N Waddington

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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.

Original languageEnglish
Article number3505
JournalNature Communications
Issue number1
Publication statusPublished - 29 Aug 2018


  • Animals
  • Argininosuccinate Lyase/genetics
  • Argininosuccinic Aciduria/genetics
  • Brain Diseases/genetics
  • Citrulline/metabolism
  • Genetic Therapy
  • Hyperammonemia/genetics
  • Liver/cytology
  • Mice
  • Neurons/metabolism
  • Nitric Oxide/metabolism
  • Nitrosative Stress/genetics


Dive into the research topics of 'Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer'. Together they form a unique fingerprint.

Cite this