Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations

Abstract

Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. Recently, unconventional non-ATG translation of the expanded hexanucleotide repeat, resulting in the production and aggregation of dipeptide repeat (DPR) proteins (poly-GA, -GR and GP), was identified as a potential pathomechanism of C9ORF72 mutations. Besides accumulation of DPR proteins, the second neuropathological hallmark lesion in C9ORF72 mutation cases is the accumulation of TDP-43. In this study, we characterized novel monoclonal antibodies against poly-GA and performed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in a cohort of 35 cases with the C9ORF72 mutation that included a broad spectrum of clinical phenotypes. We found the pattern of DPR pathology to be highly consistent among cases regardless of the phenotype with high DPR load in the cerebellum, all neocortical regions (frontal, motor cortex and occipital) and hippocampus, moderate pathology in subcortical areas and minimal pathology in lower motor neurons. No correlation between DPR pathology and the degree of neurodegeneration was observed, while a good association between TDP-43 pathology with clinical phenotype and degeneration in key anatomical regions was present. Our data confirm that the presence of DPR pathology is intimately related to C9ORF72 mutations. The observed dissociation between DPR inclusion body load and neurodegeneration might suggest inclusion body formation as a potentially protective response to cope with soluble toxic DPR species. Moreover, our data imply that alterations due to the C9ORF72 mutation resulting in TDP-43 accumulation and dysmetabolism as secondary downstream effects likely play a central role in the neurodegenerative process in C9ORF72 pathogenesis.

[18F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

“…Finally, we note that the calculation of [ 18 F]AV‐1451 BP ND data uses the superior cerebellar gray matter as a reference region, as in our other recent papers 5, 7, 9. Although across most of the genetic and sporadic forms of FTD this region remains unaffected, in previous cases with C9orf72 expansion, cerebellar atrophy and dipeptide aggregation have been described 21. In mitigation of this potential shortcoming, whilst as expected there was cerebellar gray matter atrophy in the present C9orf72, there was no observable elevated cerebellar [ 18 F]AV‐1451 signal in the uncorrected PET BP ND map.…”

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

“…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: grabbing a tiger by the tail

“…However, while this is possible-it remains to be proven, at least in a disease context. In C9 FTLD/ALS the major cell types affected are within the cerebellar cortex (granule cells), hippocampus (dentate gyrus and CA2-4 pyramidal cells), and pyramidal neurons in deeper layers of the cerebral cortex, even the occipital cortex, and various subcortical structures [1,9,39,40]. Nonetheless, the distribution of such DPR-containing cells is at odds with the known distribution of neurodegeneration in FTLD/ALS, which itself maps closely to that of TDP-43 inclusion distribution [39] (see Neumann).…”

“…In C9 FTLD/ALS the major cell types affected are within the cerebellar cortex (granule cells), hippocampus (dentate gyrus and CA2-4 pyramidal cells), and pyramidal neurons in deeper layers of the cerebral cortex, even the occipital cortex, and various subcortical structures [1,9,39,40]. Nonetheless, the distribution of such DPR-containing cells is at odds with the known distribution of neurodegeneration in FTLD/ALS, which itself maps closely to that of TDP-43 inclusion distribution [39] (see Neumann). Indeed, overlap of DPR and TDP-43 is confined to a few cells in DG, but interestingly it would appear that within such co-localisations DPR is innermost and TDP-43 outermost, suggesting DPR changes might predate, or even predispose to TDP-43 pathology [39].…”

“…Indeed, DPR can consist of any or all of the five possible species [3,21,39,40,45,47,67,69]. These DPR proteins seem to be entirely specific to the expansion, not being seen in FTLD and ALS cases without expansions [39,40], though curiously are not specific for FTLD and ALS per se with rare appearances in cases with pathologically confirmed corticobasal degeneration [40,58], AD [12,29,35] but see [15], Creutzfeldt-Jakob disease [6], and even in apparently healthy controls [6,13]. This raises issues of penetrance, or even preclinical disease [6] (see Cooper-Knock, Mead).…”