Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene

Abstract

Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks 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 without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups.Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0437-5) contains supplementary material, which is available to authorized users.

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

“…First, hnRNPA3 was found to bind to mutant C9ORF72 RNA in ALS and could mediate some of its toxic effects [146,147]. Furthermore, hnRNPA3 was also reported to be present in TDP43, p62 immunoreactive dipeptide repeat (DPR) inclusions in C9orf72 cases [148,149] further linking hnRNPA3 to C9orf72 ALS/FTD. Second, mutations in hnRNPA1 and hnRNPA2B1 have been identified in multisystem proteinopathy, a disorder combining IBM, FTD, ALS or Paget's disease of the bone (PDB) [20].…”

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

“…Moreover, the CA4 region of the hippocampus was included because this is one of the principal regions affected by DPR pathology in patients with expansions in C9orf72 [8, 22, 23]. The degree of neuronal nuclear and/or cytoplasmic hnRNP E2 immunostaining in each region was scored semi-quantitatively [9] at an objective magnification of ×25 (overall microscope magnification of ×250) employing the following rating scale:0 = No staining present.0.5 = rare (ie 1-5) cells per section showing weak nuclear and/or cytoplasmic staining.1 = few (1-5) cells showing weak nuclear and/or cytoplasmic staining per ×250 microscope field.2 = moderate number (5-10) cells showing moderate nuclear and/or cytoplasmic staining per ×250 microscope field.3 = more than 10 cells showing strong nuclear and/or cytoplasmic staining per ×250 microscope field. …”

“…Previous use of this particular scoring system has shown robust agreement in assessments when employed by both highly and lesser experienced observers [9]. …”

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

“…Recently, several hnRNPs including H1, F and M were specifically confirmed to interact with poly-PR [ 187 ]. Immunohistochemically, p62-immunoreactive DPRs have also been shown to contain hnRNP A3 [ 41 , 139 , 140 ]. This is of particular interest because nuclear depletion of hnRNP A3 in fibroblasts derived from patients carrying C9orf72 HREs led to an accumulation of nuclear RNA foci [ 41 ].…”