Tissue Iron in Friedreich Ataxia
1Research Service (151), VA Medical Center, Albany, NY 12208, USA.
Insights
Friedreich
Area of Science:
- Neuroscience
- Cardiovascular Science
- Cell Biology
Background:
- Friedreich ataxia (FA) is a rare genetic disorder characterized by progressive neurodegeneration and cardiomyopathy.
- Iron accumulation and dysregulation are implicated in FA pathogenesis, but its precise role in affected tissues remains unclear.
Purpose of the Study:
- To investigate the distribution and histopathology of iron in key tissues affected by Friedreich ataxia: the heart, dentate nucleus, and dorsal root ganglia (DRG).
Main Methods:
- Histology and histopathology of affected tissues.
- X-ray fluorescence mapping for iron distribution.
- Immunohistochemistry for ferritin and ferroportin expression.
Main Results:
- No overall increase in total iron levels was observed in affected tissues.
- Iron-reactive inclusions and aggregates were found in myocardial fibers, leading to necrosis.
- Dentate nucleus showed neuronal atrophy with iron retention in collapsed structures, alongside ferritin-positive oligodendrocytes and microglia.
- Dorsal root ganglia exhibited ferritin in satellite cells and loss of ferroportin in neurons.
Conclusions:
- Iron dysmetabolism, rather than total iron overload, contributes to tissue damage in Friedreich ataxia.
- Specific patterns of iron distribution and altered expression of iron-related proteins (ferritin, ferroportin) are observed in the heart, dentate nucleus, and DRG in FA.
- These findings highlight the complex role of iron in FA pathogenesis and suggest potential therapeutic targets.
Abstract:
Heart, dentate nucleus, and dorsal root ganglia (DRG) are targets of tissue damage in Friedreich ataxia (FA). This report summarizes the histology and histopathology of iron in the main tissues affected by FA. None of the affected anatomical sites reveals an elevation of total iron levels. In the myocardium, a small percentage of fibers shows iron-reactive granular inclusions. The accumulation of larger iron aggregates and fiber invasion cause necrosis and damage to the contractile apparatus. In the dentate nucleus, the principal FA-caused tissue injury is neuronal atrophy and grumose reaction. X-ray fluorescence mapping of iron in the dentate nucleus in FA shows retention of the metal in the center of the collapsed structure. Immunohistochemistry of ferritin, a surrogate marker of tissue iron, confirms strong expression in oligodendrocytes of the efferent white matter of the dentate nucleus and abundance of ferritin-positive microglia in the atrophic gray matter. Iron dysmetabolism in DRG is complex and consists of prominent expression of ferritin in hyperplastic satellite cells and residual nodules, also a loss of the iron export protein ferroportin from the cytoplasm of the remaining DRG nerve cells.
