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Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation.

ABSTRACT: Dorsal root ganglia (DRG) are highly vulnerable to frataxin deficiency in Friedreich ataxia (FA), an autosomal recessive disease due to pathogenic homozygous guanine-adenine-adenine trinucleotide repeat expansions in intron 1 of the FXN gene (chromosome 9q21.11). An immunohistochemical and immunofluorescence study of DRG in 15 FA cases and 12 controls revealed that FA causes major primary changes in satellite cells and inflammatory destruction of neurons. A panel of antibodies was used to reveal the cytoplasm of satellite cells (glutamine synthetase, S100, metabotropic glutamate receptors 2/3, excitatory amino acid transporter 1, ATP-sensitive inward rectifier potassium channel 10, and cytosolic ferritin), gap junctions (connexin 43), basement membranes (laminin), mitochondria (ATP synthase subunit beta and frataxin), and monocytes (CD68 and IBA1).Reaction product of the cytoplasmic markers and laminin confirmed proliferation of satellite cells and processes into multiple perineuronal layers and residual nodules. The formation of connexin 43-reactive gap junctions between satellite cells was strongly upregulated. Proliferating satellite cells in FA displayed many more frataxin- and ATP5B-reactive mitochondria than normal. Monocytes entered into the satellite cell layer, appeared to penetrate neuronal plasma membranes, and infiltrated residual nodules. Satellite cells and IBA1-reactive monocytes displayed upregulated ferritin biosynthesis, which was most likely due to leakage of iron from dying neurons.We conclude that FA differentially affects the key cellular elements of DRG, and postulate that the disease causes loss of bidirectional trophic support between satellite cells and neurons.

SUBMITTER: Koeppen AH

PROVIDER: S-EPMC4855486 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation.

Koeppen Arnulf H AH Ramirez R Liane RL Becker Alyssa B AB Mazurkiewicz Joseph E JE

Acta neuropathologica communications 20160503 1

<h4>Introduction</h4>Dorsal root ganglia (DRG) are highly vulnerable to frataxin deficiency in Friedreich ataxia (FA), an autosomal recessive disease due to pathogenic homozygous guanine-adenine-adenine trinucleotide repeat expansions in intron 1 of the FXN gene (chromosome 9q21.11). An immunohistochemical and immunofluorescence study of DRG in 15 FA cases and 12 controls revealed that FA causes major primary changes in satellite cells and inflammatory destruction of neurons. A panel of antibodi ...[more]

PMID: 27142428

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Project description:Varicella zoster virus (VZV), a human alphaherpesvirus, causes varicella during primary infection. VZV reactivation from neuronal latency may cause herpes zoster, post herpetic neuralgia (PHN) and other neurologic syndromes. To investigate VZV neuropathogenesis, we developed a model using human dorsal root ganglia (DRG) xenografts in immunodeficient (SCID) mice. The SCID DRG model provides an opportunity to examine characteristics of VZV infection that occur in the context of the specialized architecture of DRG, in which nerve cell bodies are ensheathed by satellite glial cells (SGC) which support neuronal homeostasis. We hypothesized that VZV exhibits neuron-subtype specific tropism and that VZV tropism for SGC contributes to VZV-related ganglionopathy. Based on quantitative analyses of viral and cell protein expression in DRG tissue sections, we demonstrated that, whereas DRG neurons had an immature neuronal phenotype prior to implantation, subtype heterogeneity was observed within 20 weeks and SGC retained the capacity to maintain neuronal homeostasis longterm. Profiling VZV protein expression in DRG neurons showed that VZV enters peripherin+ nociceptive and RT97+ mechanoreceptive neurons by both axonal transport and contiguous spread from SGC, but replication in RT97+ neurons is blocked. Restriction occurs even when the SGC surrounding the neuronal cell body were infected and after entry and ORF61 expression, but before IE62 or IE63 protein expression. Notably, although contiguous VZV spread with loss of SGC support would be predicted to affect survival of both nociceptive and mechanoreceptive neurons, RT97+ neurons showed selective loss relative to peripherin+ neurons at later times in DRG infection. Profiling cell factors that were upregulated in VZV-infected DRG indicated that VZV infection induced marked pro-inflammatory responses, as well as proteins of the interferon pathway and neuroprotective responses. These neuropathologic changes observed in sensory ganglia infected with VZV may help to explain the neurologic sequelae often associated with zoster and PHN.

Dataset Information

Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation.

Publications

Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation.

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