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

Yvonne S Davidson,Matthew Jones,Anna Richardson,Christian Haass,David M A Mann,Stuart Pickering-Brown,Bridget C Benson,Kohji Mori,Andrew C Robinson,Julie S Snowden,Tammaryn Lashley,Yoshihiro Nihei,Louis Flood,Sara Rollinson

doi:10.1186/s40478-017-0437-5

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.

Highlights

Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous disorder affecting principally the frontal and temporal lobes of the brain
There were no significant differences in the overall degree of TDP-43 immunostaining between FTLD-TDP type A, type B and type C groups
In the present study, we have investigated the pattern of Heterogeneous ribonuclear proteins (hnRNPs) A1, A2/B1 and A3 immunostaining across a range of clinical, pathological and genetic forms of FTLD and Motor Neurone Disease (MND)

Summary

Introduction

Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous disorder affecting principally the frontal and temporal lobes of the brain. After Alzheimer’s disease, it is the second most common neurodegenerative disorder to affect people before the age of 65 years. One syndrome is characterised by changes in behaviour and personality, accounting for around 75% of all cases of FTLD, is known as behavioural variant frontotemporal dementia (bvFTD), whereas the other two syndromes are disorders of language. Semantic dementia (SD) ( known as semantic variant of primary progressive aphasia or svPPA) is a disorder of naming and word finding, whereas Progressive Non-Fluent Aphasia (PNFA) ( known as nfvPPA) is represented by an inability to construct language such that speech becomes hesitant and stuttering, becoming grammatically and contextually incorrect [32]. The amyotrophic lateral sclerosis (ALS) form of Motor Neurone Disease (MND) is seen in about 15% of patients with bvFTD, giving FTD-MND (FTD-ALS), but is only rarely combined with either SD or PNFA [32]

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