Heterogeneous ribonuclear protein E2 (hnRNP E2) is associated with TDP-43-immunoreactive neurites in Semantic Dementia but not with other TDP-43 pathological subtypes of Frontotemporal Lobar Degeneration

Abstract

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls. Semi-quantitative analysis assessed hnRNP staining in frontal and temporal cortex, and in dentate gyrus (DG) of hippocampus, in the different pathology and genetic groups. We find that hnRNP E2 immunostaining detects the TDP-43 positive dystrophic neurites (DN) within frontal and temporal cortex, and the neuronal cytoplasmic inclusions (NCI) seen in DG granule cells, characteristic of patients with Semantic Dementia (SD) and type C TDP-43 pathology, but did not detect TDP-43 or tau inclusions in any of the other pathological or genetic variants of FTLD. Double immunofluorescence for hnRNP E2 and TDP-43 showed most TDP-43 immunopositive DN to contain hnRNP E2. Present findings indicate an association between TDP-43 and hnRNP E2 which might underlie the pathogenetic mechanism of this form of FTLD.

HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing

“…Mislocalisation of hnRNP K occurs in neurons that are distinct from those which harbour proteinaceous TDP-43 and Tau inclusions that pathologically define FTLD subtypes. This is novel compared to previous work which has identified several other hnRNPs to be present within TDP-43 and FUS inclusions [ 15 , 24 ]. There is also an abundance of research on hnRNPs co-depositing with C9orf72-associated pathologies including RNA foci and dipeptide repeat proteins [ 13 , 14 , 25 , 59 ].…”

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

“…By contrast, the pattern of TDP-43 deposition across the FTLD-TDP pathological spectrum is far more heterogeneous with a variety of morphologically distinct cytoplasmic and intranuclear TDP-43 immunoreactive inclusions characterising five molecular sub-types [ 111 ]. HnRNP E2 has been shown to colocalise in FTLD-TDP type C inclusions associated with semantic dementia [ 42 ] and more recently, type A inclusions [ 89 ].…”

“…Immunohistochemical studies have confirmed a colocalisation between hnRNP E2 and specific TDP-43 pathologies in FTLD-TDP type C and type A pathologies in postmortem brain tissue [ 42 , 89 ]. Whilst the FTLD-TDP subtype-specificity of hnRNP E2 inclusion remains enigmatic; its potential sequestration within TDP-43 aggregates is further evidence for hnRNP functional deficit within FTLD pathogenesis.…”

Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases

“…It was also found in ALS patients that hnRNP A1, along with TDP-43, had a greater tendency to aggregate in the cytoplasmic inclusions compared to controls [ 150 ]. Another hnRNP, E2, also co-localized with TDP-43 in pathological inclusions of the semantic dementia subtype FTD patients [ 151 ] (Fig. 3 ).…”