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.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-70) contains supplementary material, which is available to authorized users.

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

“…These are illustrated in Figure 1 (and Table 2) with reference to the three Newcastle cases, although similar changes were seen in the Manchester cohort, and these have been described and presented elsewhere (see supplementary Figure S1 and [11, 13]).…”

“…The 13 Manchester patients with FTLD, known to bear expansions in C9ORF72 , have been reported elsewhere [11, 13]. In all 16 expansion carriers, expansion size ranged from ∼5 kb (∼450 repeats) to in excess of 23 kb over 3600 repeats).…”

“…In addition brains were also available from the Manchester Brain Bank (MBB) from 13 other patients with FTLD (cases #23–35, eight men, five women) known to bear expansions in C9ORF72 [11, 13] from the North West of England and North Wales (supplementary Table S1). All 35 patients fulfilled Lund‐Manchester clinical diagnostic criteria for FTLD [2, 17].…”

“…However, more recent studies have frequently reported a significant proportion of C9ORF72 mutation cases to have other patterns of FTLD‐TDP, most often type A [9, 11, 15], and rarely type C [16]. Nonetheless, all cases bearing expansions appear to show a similar and characteristic DPR pathology irrespective of what TDP‐43 histological type may also be present [13, 14]. …”

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

“…One of the main hypotheses regarding its function propose a similar function to guanine nucleotide exchange factors for small GTPases associated with the regulation of Rab protein system during endosomal trafficking regulation of exocytosis and endocytosis (with the Rab protein system) in neuronal cell lines, primary cortical neurons and spinal cord motor neurons. It gives rise to a higher rate of lysosomal protein degradation and abnormal accumulation of ubiquinated proteins 26 . The C9orf72 encoded protein also participates in mechanisms of neuronal autophagic process and interacts with nuclear proteins involved with regulation of splicing and RNA metabolism 18 .…”