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Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer

Author

Listed:
  • Julien Baruteau

    (University College London
    Great Ormond Street Hospital for Children NHS Foundation Trust
    University College London)

  • Dany P. Perocheau

    (University College London)

  • Joanna Hanley

    (University College London
    University College London)

  • Maëlle Lorvellec

    (University College London
    University College London)

  • Eridan Rocha-Ferreira

    (University College London)

  • Rajvinder Karda

    (University College London)

  • Joanne Ng

    (University College London
    Great Ormond Street Hospital for Children NHS Foundation Trust)

  • 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
    Great Ormond Street Hospital for Children NHS Foundation Trust)

  • 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
    University College London
    University College London)

  • Simon N. Waddington

    (University College London
    University of the Witswatersrand)

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.

Suggested Citation

  • 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 & Bl, 2018. "Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05972-1
    DOI: 10.1038/s41467-018-05972-1
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    Cited by:

    1. Clément Pontoizeau & Marcelo Simon-Sola & Clovis Gaborit & Vincent Nguyen & Irina Rotaru & Nolan Tual & Pasqualina Colella & Muriel Girard & Maria-Grazia Biferi & Jean-Baptiste Arnoux & Agnès Rötig & , 2022. "Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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