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The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins

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Abstract

Frataxin deficiency in Friedreich’s ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal controls by biochemical and microscopic techniques. Total iron (1.53 ± 0.53 μmol/g wet weight) and ferritin (206.9 ± 46.6 μg/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 ± 0.88 μmol/g; ferritin: 210.9 ± 9.0 μg/g) but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 confirmed neuronal loss while endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers. Neuronal loss in the dentate nucleus is the likely result of trans-synaptic degeneration.

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Acknowledgments

Dr. Koeppen’s laboratory is supported, in part, by the Office of Research and Development (Laboratory Medicine R&D Service) of the Department of Veterans Affairs, Washington, DC, USA. The authors received financial support from Friedreich’s Ataxia Research Alliance, Alexandria, VA, USA (AHK); National Ataxia Foundation, Minneapolis, MN, USA (AHK); Neurochemical Research, Inc., Glenmont, NY, USA (AHK); and NIH grants R01DLK59794 (MDG) and DK065064 (MDK).

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Authors and Affiliations

  1. Research, Veterans Affairs Medical Center, Albany, NY, USA

    Arnulf H. Koeppen & Susan C. Michael

  2. Neurology, Veterans Affairs Medical Center, Albany, NY, USA

    Arnulf H. Koeppen & Jiang Qian

  3. Pathology Service, Veterans Affairs Medical Center, Albany, NY, USA

    Arnulf H. Koeppen & Jiang Qian

  4. Departments of Neurology and Pathology, Albany Medical College, Albany, NY, USA

    Arnulf H. Koeppen & Jiang Qian

  5. Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, USA

    Mitchell D. Knutson

  6. Veterans Affairs Medical Center and University of Texas Health Sciences Center, San Antonio, TX, USA

    David J. Haile

  7. San Raffaele Scientific Institute, Milan, Italy

    Sonia Levi & Paolo Santambrogio

  8. Vita-Salute San Raffaele University, Milan, Italy

    Sonia Levi

  9. Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA

    Michael D. Garrick

  10. Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada

    Jacques B. Lamarche

  11. Neurology Service (528A/127), Stratton VA Medical Center, 113 Holland Ave, Albany, NY, 12208, USA

    Arnulf H. Koeppen

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  1. Arnulf H. Koeppen
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  2. Susan C. Michael
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  4. David J. Haile
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  5. Jiang Qian
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  6. Sonia Levi
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  7. Paolo Santambrogio
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  9. Jacques B. Lamarche
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Correspondence to Arnulf H. Koeppen.

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Koeppen, A.H., Michael, S.C., Knutson, M.D. et al. The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins. Acta Neuropathol 114, 163–173 (2007). https://doi.org/10.1007/s00401-007-0220-y

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  • DOI: https://doi.org/10.1007/s00401-007-0220-y

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