Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions inC9ORF72gene
| Autor: | Yvonne S Davidson, Robert H. Perry, Stuart Pickering-Brown, Masato Hasegawa, David M. A. Mann, Sara Rollinson, Ian G. McKeith, Evelyn Jaros, Masami Masuda-Suzukake, Timothy D. Griffiths, Andrew C Robinson, David J. Burn, Atik Baborie |
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| Rok vydání: | 2015 |
| Předmět: |
Pathology
medicine.medical_specialty Cerebellum Histology Biology Hippocampal formation Inclusion bodies Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine C9orf72 Physiology (medical) mental disorders medicine 030304 developmental biology 0303 health sciences nutritional and metabolic diseases Frontotemporal lobar degeneration DNA Repeat Expansion medicine.disease nervous system diseases C9orf72 Protein medicine.anatomical_structure Neurology Neurology (clinical) Trinucleotide repeat expansion 030217 neurology & neurosurgery |
| Zdroj: | Neuropathology and Applied Neurobiology. 41:601-612 |
| ISSN: | 0305-1846 |
| DOI: | 10.1111/nan.12178 |
| Popis: | AIMS: Frontotemporal lobar degeneration (FTLD) and Motor Neuron Disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, 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. METHODS: Twenty two cases of FTLD from Newcastle were analyzed for an expansion in C9ORF72 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 to that in 13 other previously identified cases from the Manchester Brain Bank with established disease. RESULTS: Three Newcastle patients bearing an expansion in C9ORF72 were identified. These 3 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 3 patients was similar to that in the Manchester series, though the extent of TDP-43 pathology was significantly less. CONCLUSION: Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72. |
| Databáze: | OpenAIRE |
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