Abstract
AimsA hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain.MethodsUsing antibodies to poly‐GA, poly‐GP, poly‐GR, poly‐AP and poly‐PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR).ResultsAntibodies to poly‐GA, poly‐GP and poly‐GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as ‘star‐burst’ shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly‐PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly‐PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly‐GA antibody generally detected more DPR than poly‐GP, which in turn was greater than poly‐GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP‐43 positive inclusions in remaining anterior horn cells.ConclusionDegeneration and loss of anterior horn cells associated with expansions in C9orf72 occurs in the absence of DPR, and implies that changes involving loss of nuclear staining for and a cytoplasmic aggregation of TDP‐43 are more likely to be the cause of this.
Highlights
The major genetic cause of familial frontotemporal lobar degeneration (FTLD), and of familial motor neurone disease (MND), is associated with the possession of a hexanucleotide expansion in C9orf72 gene, this occurring in about 20% cases of familial FTLD and 80% cases of familial MND [1,2]
The first group of 20 patients [five patients #1–5 with behavioural variant Frontotemporal dementia, six patients #6–11 with bvFTD combined with MND and nine patients #12–20 with MND alone] (Table S1) all bore an expansion in C9orf72 (Table S1)
Hippocampus and cerebellum As we have reported previously [11,22], TDP-43 negative, p62-positive neuronal cytoplasmic inclusions (NCI) were widely present in the hippocampus and cerebellum of all individuals bearing an expansion in C9orf72 irrespective of clinical or pathological diagnosis, but none were seen in these cells in any of those MND individuals without an expansion in C9orf72, nor in any of the controls
Summary
The major genetic cause of familial frontotemporal lobar degeneration (FTLD), and of familial motor neurone disease (MND), is associated with the possession of a hexanucleotide expansion in C9orf gene, this occurring in about 20% cases of familial FTLD and 80% cases of familial MND [1,2]. The discovery of this genetic change has spawned a wealth of new knowledge and observation, the exact pathological mechanism(s) underlying the expansion in C9orf remains uncertain. How any of these potential effects might translate into the TDP-43 proteinopathy that characterises both conditions remains to be established
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