Friedreich Ataxia

Abstract

Atrophy of large neurons in the dentate nucleus (DN) is an important pathological correlate of neurological disability in patients with Friedreich ataxia (FA). Thinning of the DN was quantified in 29 autopsy cases of FA and 2 carriers by measuring the thickness of the gray matter ribbon on stains with anti-glutamic acid decarboxylase (GAD), the rate-limiting enzyme in the biosynthesis of γ-amino-butyric acid (GABA). The DN was thinner than normal in all cases of FA, and atrophy correlated inversely with disease duration but not with age of onset or length of the homozygous guanine-adenine-adenine trinucleotide expansions. In 13 of the FA cases, frozen DN tissue was available for assay of frataxin. DN atrophy was more severe when frataxin was very low. Immunohistochemical staining for GAD revealed grumose reaction and preservation of small GABA-ergic neurons in the DN of FA patients. Residual small DN neurons and varicose axons also contained the glycine transporter 2, identifying them as glycinergic. Immunohistochemistry also confirmed severe loss of GABA-A and glycine receptors in the DN with comparable depletion of the receptor-anchoring protein gephyrin. Thus, loss of gephyrin and failure to position GABA-A and glycine receptors correctly may reduce trophic support of large DN neurons and contribute to their atrophy. By contrast, Purkinje cells may escape retrograde atrophy in FA by issuing new axonal sprouts to small surviving DN neurons where they form reparative grumose clusters.

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study

“…In the brainstem and cerebellum, correlations with onset age were evident in the pons, while associations with disease severity were more consistently found in peri-dentate regions. Notably, recent neuropathological evidence suggests that spinal cord pathology in FRDA results from compromised development, whereas dentate pathology reflects degeneration (Koeppen et al, 2017;Koeppen, Ramirez, Becker, Feustel, & Mazurkiewicz, 2015). However, our observation of subthreshold age of onset correlations in peri-dentate regions cautions against interpreting onset and severity correlations as exclusively impacting different brain regions.…”

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

“…), and antigen retrieval methods. Details of immunohistochemistry and double-label immunofluorescence of DRG were described in previous publications [ 13 – 16 ]. Briefly, for immunohistochemistry, paraffin sections were rehydrated and oxidized in hydrogen peroxide-containing methanol, processed through antigen retrieval (Table 1 ), blocked by 10 % normal horse serum in phosphate-buffered saline (PBS), and incubated overnight at 4 °C in antibodies (Table 1 ) diluted in PBS, also containing 1 % normal horse serum.…”

“…Four proteins listed in Table 1 (ATP5B, connexin 43, EAAT1, and IBA1) were validated by tandem mass spectrometry including multiple reaction monitoring-initiated detection and sequencing (MIDAS), as described by Unwin et al [ 28 ]. For this purpose, proteins in samples of frozen DRG (35–65 mg) were extracted by ultrasonication in a buffer found suitable for the assay of tissue frataxin [ 5 , 16 ]. After centrifugation at 14,000 × g for 45 min, the supernatant was collected, and an aliquot was used for sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting by established procedures.…”

The neuropathology of the adult cerebellum

“…Small neurons are GAD-reactive (Fig. 8.1F), though the DN also contains small glycinergic nerve cells (Koeppen et al, 2015). The small GABAergic neurons in the DN provide most, if not all, GABAergic input to the ION (Fig.…”

“…The author prefers grumose “reaction” over the more widely used term “degeneration” because the GAD-reactive clusters (Fig. 8.3H) also react strongly with antisynaptophysin, supporting proliferation of synaptic terminals (Koeppen et al, 2015). While neurons in the DN must still have intact dendrites to present sites for proliferation of axon terminals, the clusters ultimately disappear.…”