Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene. (30th April 2015)

• Record Type: Journal Article
• Authors: Baborie, Atik; Griffiths, Timothy D.; Jaros, Evelyn; Perry, Robert; McKeith, Ian G.; Burn, David J.; Masuda‐Suzukake, Masami; Hasegawa, Masato; Rollinson, Sara; Pickering‐Brown, Stuart; Robinson, Andrew C.; Davidson, Yvonne S.; Mann, David M. A.
• Is Part Of: Neuropathology & applied neurobiology. Volume 41:Number 5(2015)
• Page Start: 601
• Page End: 612
• Publication Date: 2015-04-30
• Subjects: Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12178
• Languages: English
• ISSNs: 0305-1846

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="nan12178-sec-0001" sec-type="section"> <title>Aims</title> <p>Frontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in <italic>C9ORF72</italic>, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP‐43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non‐ATG RAN translation of the expanded region of the gene.</p> </sec> <sec id="nan12178-sec-0002" sec-type="section"> <title>Methods</title> <p>Twenty‐two cases of FTLD from Newcastle were analysed for an expansion in <italic>C9ORF72</italic> by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP‐43, p62 and DPR. The extent of TDP‐43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease.</p> </sec> <sec id="nan12178-sec-0003" sec-type="section"> <title>Results</title> <p>Three Newcastle patients bearing an expansion in <italic>C9ORF72</italic> were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP‐43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP‐43 pathology was significantly less.</p> </sec> <sec id="nan12178-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP‐43 in patients with FTLD bearing expansion in <italic>C9ORF72</italic>.</p> </sec> </abstract>