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Friedreich ataxia: metal dysmetabolism in dorsal root ganglia (651.1)
Author(s) -
Mazurkiewicz Joseph,
Ramirez R Liane,
Koeppen Arnulf
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.651.1
Subject(s) - metallothionein , dorsal root ganglion , reactive oxygen species , ataxia , mitochondrion , microbiology and biotechnology , chemistry , biology , biochemistry , neuroscience , anatomy , dorsum , gene
Friedreich ataxia (FA) is caused by an inherited deficiency of frataxin, a small nuclear genome‐encoded mitochondrial protein and leads to Fe related mitochondrial dysfunction. Atrophy of large dorsal root ganglion (DRG) neurons, hyperplasia of satellite cells, and absorption of dying neurons into residual nodules are hallmarks of FA. Dysregulation of antioxidant defenses due to over production of reactive oxygen species by transition metals (e.g. Zn and Fe) has been implicated in FA pathology. Tissue levels of Fe and Zn in normal and FA DRG did not differ significantly, however, the Zn level found, ~90.24 μM, is much higher than needed for normal function of Zn‐dependent proteins and the disturbance of Zn buffering could lead to mitochondrial damage and cell death. The Zn‐transporter, Zip14 (neurons & satellite cells), metallothionein MT1/2 (Zn; satellite cells), metallothionein 3, MT3 (Zn; neurons), and ferritin (Fe) were used as surrogates for Zn and Fe. Major shifts in Zip14 and MT1/2 immunofluorescence between neurons and satellite cells in FA DRG suggests that the metals released from dying neurons move into the proliferating satellite cells. In contrast to Zn, sequestration of Fe in satellite cells may represent a protective mechanism. Changes in the expression and cellular localization of metal handling proteins link metal dysmetabolism with the pathogenesis of the DRG lesion in FA. Grant Funding Source : Supported by grant from National Institutes of Health (R01‐NS069454), Bethesda, MD, USA