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Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer.

Nat Commun. 2018 Aug 29;9(1):3505
Julien Baruteau 1 , Dany P Perocheau 2 , Joanna Hanley 3 , Maëlle Lorvellec 3 , Eridan Rocha-Ferreira 4 , Rajvinder Karda 2 , Joanne Ng 5 , Natalie Suff 2 , Juan Antinao Diaz 2 , Ahad A Rahim 6 , Michael P Hughes 6 , Blerida Banushi 3 , Helen Prunty 7 , Mariya Hristova 4 , Deborah A Ridout 8 , Alex Virasami 9 , Simon Heales 7 , Stewen J Howe 2 , Suzanne M K Buckley 2 , Philippa B Mills 1 , Paul Gissen 3 , Simon N Waddington 10
Julien Baruteau 1 , Dany P Perocheau 2 , Joanna Hanley 3 , Maëlle Lorvellec 3 , Eridan Rocha-Ferreira 4 , Rajvinder Karda 2 , Joanne Ng 5 , Natalie Suff 2 , Juan Antinao Diaz 2 , Ahad A Rahim 6 , Michael P Hughes 6 , Blerida Banushi 3 , Helen Prunty 7 , Mariya Hristova 4 , Deborah A Ridout 8 , Alex Virasami 9 , Simon Heales 7 , Stewen J Howe 2 , Suzanne M K Buckley 2 , Philippa B Mills 1 , Paul Gissen 3 , Simon N Waddington 10
+ et al

[No authors listed]

Author information
  • 1 Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
  • 2 Gene Transfer Technology Group, Institute for Women's Health, University College London, 86-96 Chenies Mews, London, WC1E 6HX, UK.
  • 3 MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
  • 4 Perinatal Brain Repair Group, Institute for Women's Health, University College London, 86-96 Chenies Mews, London, WC1E 6HX, UK.
  • 5 Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • 6 Department of Pharmacology, School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
  • 7 Department of Paediatric Laboratory Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • 8 Population, Policy and Practice Programme, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1E, UK.
  • 9 Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • 10 Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witswatersrand, Johannesburg, South Africa. s.waddington@ucl.ac.uk.

摘要


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.