• Open Access

Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy

Authors

  • Jone López-Erauskin MSc,

    1. Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research (IDIBELL), Hospitalet de Liobregat, Barcelona, Spain
    2. The Centre Biomedical Network Research on Rare Diseases (CIBERER), The Spanish Institute for Health Carlos III (ISCIII), Barcelona, Spain
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  • Stéphane Fourcade PhD,

    1. Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research (IDIBELL), Hospitalet de Liobregat, Barcelona, Spain
    2. The Centre Biomedical Network Research on Rare Diseases (CIBERER), The Spanish Institute for Health Carlos III (ISCIII), Barcelona, Spain
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  • Jorge Galino MSc,

    1. Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research (IDIBELL), Hospitalet de Liobregat, Barcelona, Spain
    2. The Centre Biomedical Network Research on Rare Diseases (CIBERER), The Spanish Institute for Health Carlos III (ISCIII), Barcelona, Spain
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  • Montserrat Ruiz PhD,

    1. Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research (IDIBELL), Hospitalet de Liobregat, Barcelona, Spain
    2. The Centre Biomedical Network Research on Rare Diseases (CIBERER), The Spanish Institute for Health Carlos III (ISCIII), Barcelona, Spain
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  • Agatha Schlüter PhD,

    1. Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research (IDIBELL), Hospitalet de Liobregat, Barcelona, Spain
    2. The Centre Biomedical Network Research on Rare Diseases (CIBERER), The Spanish Institute for Health Carlos III (ISCIII), Barcelona, Spain
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  • Alba Naudi PhD,

    1. Experimental Medicine Department, University of Lieida-IRB-LLEIDA (Biomedical Research Institute of Lieida), Lieida, Spain
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  • Mariona Jove PhD,

    1. Experimental Medicine Department, University of Lieida-IRB-LLEIDA (Biomedical Research Institute of Lieida), Lieida, Spain
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  • Manuel Portero-Otin MD, PhD,

    1. Experimental Medicine Department, University of Lieida-IRB-LLEIDA (Biomedical Research Institute of Lieida), Lieida, Spain
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  • Reinald Pamplona MD, PhD,

    1. Experimental Medicine Department, University of Lieida-IRB-LLEIDA (Biomedical Research Institute of Lieida), Lieida, Spain
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  • Isidre Ferrer MD, PhD,

    1. Neuropathology Institute, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain
    2. The Centre for Biomedical Network Research on Neurodegenerative Diseases (CIBERNED), The Spanish Institute for Health Carlos III (ISCIII), Barcelona, Spain
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  • Aurora Pujol MD, PhD

    Corresponding author
    1. Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research (IDIBELL), Hospitalet de Liobregat, Barcelona, Spain
    2. The Centre Biomedical Network Research on Rare Diseases (CIBERER), The Spanish Institute for Health Carlos III (ISCIII), Barcelona, Spain
    3. Neuropathology Institute, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain
    4. Catalan Institution of Research and Advanced Studies, Barcelona, Spain
    • Neurometabolic Disease Lab, IDIBELL, Hospital Duran i Reynals, Gran Via 199, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
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Abstract

Objective:

Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD).

Methods:

X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD.

Results:

Here, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.

Interpretation:

We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor. Ann Neurol 2011;

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