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. Mills, Paul Gissen and Simon N. Waddington ()
Additional contact information
Julien Baruteau: University College London
Dany P. Perocheau: University College London
Joanna Hanley: University College London
Maëlle Lorvellec: University College London
Eridan Rocha-Ferreira: University College London
Rajvinder Karda: University College London
Joanne Ng: University College London
Natalie Suff: University College London
Juan Antinao Diaz: University College London
Ahad A. Rahim: University College London
Michael P. Hughes: University College London
Blerida Banushi: University College London
Helen Prunty: Great Ormond Street Hospital for Children NHS Foundation Trust
Mariya Hristova: University College London
Deborah A. Ridout: University College London
Alex Virasami: Great Ormond Street Hospital for Children NHS Foundation Trust
Simon Heales: University College London
Stewen J. Howe: University College London
Suzanne M. K. Buckley: University College London
Philippa B. Mills: University College London
Paul Gissen: Great Ormond Street Hospital for Children NHS Foundation Trust
Simon N. Waddington: University College London

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05972-1

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