The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins
- PMID: 17443334
- DOI: 10.1007/s00401-007-0220-y
The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins
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 mumol/g wet weight) and ferritin (206.9 +/- 46.6 mug/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 +/- 0.88 mumol/g; ferritin: 210.9 +/- 9.0 mug/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.
Similar articles
-
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.Acta Neuropathol. 2010 Jul;120(1):97-108. doi: 10.1007/s00401-010-0675-0. Epub 2010 Mar 26. Acta Neuropathol. 2010. PMID: 20339857
-
The dorsal root ganglion in Friedreich's ataxia.Acta Neuropathol. 2009 Dec;118(6):763-76. doi: 10.1007/s00401-009-0589-x. Epub 2009 Aug 30. Acta Neuropathol. 2009. PMID: 19727777
-
Friedreich's ataxia causes redistribution of iron, copper, and zinc in the dentate nucleus.Cerebellum. 2012 Dec;11(4):845-60. doi: 10.1007/s12311-012-0383-5. Cerebellum. 2012. PMID: 22562713 Free PMC article.
-
Mitochondrial pathophysiology in Friedreich's ataxia.J Neurochem. 2013 Aug;126 Suppl 1:53-64. doi: 10.1111/jnc.12303. J Neurochem. 2013. PMID: 23859341 Review.
-
Cardiomyopathy in Friedreich's ataxia.Acta Neurol Belg. 2011 Sep;111(3):183-7. Acta Neurol Belg. 2011. PMID: 22141280 Review.
Cited by
-
Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion?Antioxidants (Basel). 2020 Jul 24;9(8):664. doi: 10.3390/antiox9080664. Antioxidants (Basel). 2020. PMID: 32722309 Free PMC article. Review.
-
The in vivo reduction of afferent facilitation induced by low frequency electrical stimulation of the motor cortex is antagonized by cathodal direct current stimulation of the cerebellum.Cerebellum Ataxias. 2016 Aug 30;3(1):15. doi: 10.1186/s40673-016-0053-3. eCollection 2016. Cerebellum Ataxias. 2016. PMID: 27579172 Free PMC article.
-
Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?Pharmaceuticals (Basel). 2018 Sep 19;11(3):89. doi: 10.3390/ph11030089. Pharmaceuticals (Basel). 2018. PMID: 30235822 Free PMC article. Review.
-
Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry.J Neurosci Res. 2020 Nov;98(11):2219-2231. doi: 10.1002/jnr.24701. Epub 2020 Jul 30. J Neurosci Res. 2020. PMID: 32731306 Free PMC article.
-
Visualizing the deep cerebellar nuclei using quantitative susceptibility mapping: An application in healthy controls, Parkinson's disease patients and essential tremor patients.Hum Brain Mapp. 2023 Mar;44(4):1810-1824. doi: 10.1002/hbm.26178. Epub 2022 Dec 11. Hum Brain Mapp. 2023. PMID: 36502376 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical