title: Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.
abstract: A hexanucleotide (GGGGCC) expansion in C9ORF72 gene is the most common genetic change seen in familial Frontotemporal Lobar Degeneration (FTLD) and familial Motor Neurone Disease (MND). Pathologically, expansion bearers show characteristic p62 positive, TDP-43 negative inclusion bodies within cerebellar and hippocampal neurons which also contain dipeptide repeat proteins (DPR) formed from sense and antisense RAN (repeat associated non ATG-initiated) translation of the expanded repeat region itself. 'Inappropriate' formation, and aggregation, of DPR might therefore confer neurotoxicity and influence clinical phenotype. Consequently, we compared the topographic brain distribution of DPR in 8 patients with Frontotemporal dementia (FTD), 6 with FTD + MND and 7 with MND alone (all 21 patients bearing expansions in C9ORF72) using a polyclonal antibody to poly-GA, and related this to the extent of TDP-43 pathology in key regions of cerebral cortex and hippocampus. There were no significant differences in either the pattern or severity of brain distribution of DPR between FTD, FTD + MND and MND groups, nor was there any relationship between the distribution of DPR and TDP-43 pathologies in expansion bearers. Likewise, there were no significant differences in the extent of TDP-43 pathology between FTLD patients bearing an expansion in C9ORF72 and non-bearers of the expansion. There were no association between the extent of DPR pathology and TMEM106B or APOE genotypes. However, there was a negative correlation between the extent of DPR pathology and age at onset. Present findings therefore suggest that although the presence and topographic distribution of DPR may be of diagnostic relevance in patients bearing expansion in C9ORF72 this has no bearing on the determination of clinical phenotype. Because TDP-43 pathologies are similar in bearers and non-bearers of the expansion, the expansion may act as a major genetic risk factor for FTLD and MND by rendering the brain highly vulnerable to those very same factors which generate FTLD and MND in sporadic disease.
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Davidson
authors.forename: Holly
authors.initials: H
authors.lastname: Barker
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Robinson
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Thompson
authors.forename: Jenny
authors.initials: J
authors.lastname: Harris
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Saraj
authors.forename: Chris
authors.initials: C
authors.lastname: Shaw
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.forename: Masami
authors.initials: M
authors.lastname: Masuda-Suzukake
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Stuart
authors.initials: S
authors.lastname: Pickering-Brown
authors.forename: Julie S
authors.initials: JS
authors.lastname: Snowden
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford M6 8HD, UK. david.mann@manchester.ac.uk.
authors.forename: David M
authors.initials: DM
authors.lastname: Mann
mesh_terms: D000328:Adult; D000368:Aged; D001057:Apolipoproteins E; D001921:Brain / Q000378:metabolism*; D000073885:C9orf72 Protein; D004252:DNA Mutational Analysis; D042622:DNA Repeat Expansion / Q000235:genetics*; D004268:DNA-Binding Proteins; D004151:Dipeptides / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology*; D011506:Proteins / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D004151:Dipeptides; D011506:Proteins