Dorsal root ganglia in Friedreich ataxia: the critical role of - PowerPoint PPT Presentation

Dorsal root ganglia in Friedreich ataxia: the critical role of satellite cells Arnulf H. Koeppen, R. Liane Ramirez, Alyssa B. Becker, and Joseph E. Mazurkiewicz Albany, N.Y., USA

Friedreich ataxia (FRDA) Definition: An autosomal recessive ataxia due to homozygous guanine-adenine-adenine trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene on chromosome 9q21.11, causing impaired transcription and lack of a small mitochondrial protein, frataxin. Prevalence: 1:40,000 – 1:140,000 (Western European peoples); total in USA, 6,000-10,000 Disease targets: Motor cortex; dentate nucleus; dorsal root ganglia (DRG); sensory nerve; heart; β -cells of the pancreas This study: DRG of Friedreich ataxia (15 cases); normal Nikolaus Friedreich controls (12) 1825-1882

Norma l FRDA Normal, class-III- β -tubulin FRDA, class-III- β -tubulin

Normal, laminin 2 FRDA, laminin 2

Normal, GFAP FRDA, GFAP Normal, glutamine synthetase FRDA, glutamine synthetase

FRDA, S100 α Normal, S100 Normal, connexin 43 FRDA, connexin 43

Normal S100 Normal connexin 43 Normal merged FRDA S100 FRDA connexin 43 FRDA merged

Normal, mGluR1 α FRDA, mGluR1 α Normal, mGluR2/3 FRDA, mGluR2/3

Normal, EAAT1 FRDA, EAAT1 Normal, Kir4.1 FRDA, Kir4.1

FRDA, IBA1 Normal, IBA1 Normal, CD68 FRDA, CD68

Normal S100/IBA1 FRDA S100/IBA1

FRDA, frataxin Normal, frataxin FRDA, ATP5B Normal, ATP5B

Key observations: (1)Hypertrophy and hyperplasia of satellite cells expressing glutamine synthetase, S100, the gap junction protein connexin 43, basement membrane material (laminin-2), GFAP, EAAT1, Kir4.1, frataxin, and ATP5B (2)Infiltration of DRG by monocytes and neuronal invasion (IBA1 and CD68) Conclusions The traditional interpretation that FRDA causes “atrophy” of DRG neurons must be modified. Lack of frataxin causes generalized morphological abnormalities of satellite cells, disturbing their trophic interaction with neurons. Neuronal destruction is due to inflammatory infiltration and invasion by monocytes rather than “atrophy”. Acknowledgments Supported by NIH and Friedreich’s Ataxia Research Alliance