Apoptosis-inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxins

Authors

  • Celine Perier PhD,

    1. Vall d'Hebron Research Institute and Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
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  • Jordi Bové PhD,

    1. Vall d'Hebron Research Institute and Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
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  • Benjamin Dehay PhD,

    1. Vall d'Hebron Research Institute and Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
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  • Vernice Jackson-Lewis PhD,

    1. Department of Neurology, Columbia University, New York, NY
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  • Peter S. Rabinovitch MD, PhD,

    1. Department of Pathology, University of Washington, Seattle, WA
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  • Serge Przedborski MD, PhD,

    1. Department of Neurology, Columbia University, New York, NY
    2. Department of Pathology, Columbia University, New York, NY
    3. Department of Cell Biology, Columbia University, New York, NY
    4. Center for Motor Neuron Biology and Disease, Columbia University, New York, NY
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  • Miquel Vila MD, PhD

    Corresponding author
    1. Vall d'Hebron Research Institute and Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
    2. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
    • Neurodegenerative Diseases Research Group, Research Institute of the University Hospital Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
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Abstract

Objective

Mitochondrial complex I deficits have long been associated with Parkinson disease (PD). However, it remains unknown whether such defects represent a primary event in dopaminergic neurodegeneration.

Methods

Apoptosis-inducing factor (AIF) is a mitochondrial protein that, independently of its proapoptotic properties, plays an essential physiologic role in maintaining a fully functional complex I. We used AIF-deficient harlequin (Hq) mice, which exhibit structural deficits in assembled complex I, to determine whether primary complex I defects linked to AIF depletion may cause dopaminergic neurodegeneration.

Results

Despite marked reductions in mitochondrial complex I protein levels, Hq mice did not display apparent alterations in the dopaminergic nigrostriatal system. However, these animals were much more susceptible to exogenous parkinsonian complex I inhibitors, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Subtoxic doses of MPTP, unable to cause damage to wild-type animals, produced marked nigrostriatal dopaminergic degeneration in Hq mice. This effect was associated with exacerbated complex I inhibition and increased production of mitochondrial-derived reactive oxygen species (ROS) in Hq brain mitochondria. The antioxidant superoxide dismutase-mimetic compound tempol was able to reverse the increased susceptibility of Hq mice to MPTP. Supporting an instrumental role for mitochondrial-derived ROS in PD-related neurodegeneration, transgenic mice overexpressing mitochondrially targeted catalase exhibited an attenuation of MPTP-induced mitochondrial ROS and dopaminergic cell death.

Interpretation

Structural complex I alterations linked to AIF deficiency do not cause dopaminergic neurodegeneration but increase the susceptibility of dopaminergic neurons to exogenous parkinsonian neurotoxins, reinforcing the concept that genetic and environmental factors may interact in a common molecular pathway to trigger PD. ANN NEUROL 2010;68:184–192

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