Heterogeneous nuclear ribonucleoproteins R and Q accumulate in pathological inclusions in FTLD-FUS

Lauren M Gittings,Sandrine C Foti,Adrian M Isaacs,Bridget C Benson,Tammaryn Lashley,Priya Gami-Patel

doi:10.1186/s40478-019-0673-y

Abstract

Frontotemporal lobar degeneration (FTLD) is pathologically subdivided based on the presence of particular pathological proteins that are identified in inclusion bodies observed post-mortem. The FTLD-FUS subgroup is defined by the presence of the fused in sarcoma protein (FUS) in pathological inclusions. FUS is a heterogeneous nuclear ribonucleoprotein (hnRNP) protein and a member of the FET (FUS, EWS, TAF15) protein family. It shuttles between the nucleus and cytoplasm, and has been implicated in many cellular functions including translation, splicing, and RNA transport. EWS, TAF15 and the nuclear import receptor transportin have been shown to co-accumulate with FUS in neuronal inclusions specifically in FTLD-FUS, with transportin-positive inclusions most frequently observed. Here, we report the identification of hnRNP R and hnRNP Q in neuronal cytoplasmic and intranuclear inclusions in the frontal cortex and hippocampus of FTLD-FUS patients, as frequently as transportin. hnRNP R and hnRNP Q were not found in the characteristic pathological inclusions observed in FTLD-TDP (subtypes A-C). Additionally, we studied the expression of hnRNP R in the frontal and temporal cortices from patients with FTLD and found significantly increased expression of the heterogeneous nuclear ribonucleoprotein R in several FTLD disease groups. Our identification of the frequent presence of hnRNP R and hnRNP Q in FTLD-FUS inclusions suggests a potential role for these hnRNPs in FTLD-FUS pathogenesis and supports the role of dysfunctional RNA metabolism in FTLD.

Highlights

Frontotemporal lobar degeneration (FTLD) is a broad term used to describe the major pathology underlying a clinically heterogeneous group of neurodegenerative diseases characterised by progressive changes in executive function, behaviour and/or language
Strong neuronal nuclear staining of heterogeneous nuclear ribonucleoprotein (hnRNP) R and hnRNP Q was observed in was identified in FTLD-TDP A (p = 0.0005, n = 19), FTLD-TDP C (p = 0.0036, n = 7) and FTLD-fused in sarcoma (FUS) (p = 0.0048, n = 5) compared to controls (n = 6)
HnRNP Q are mislocalised into pathological inclusions in two subtypes of FTLD-FUS, expanding the spectrum of DNA/RNA binding proteins linked to FTLD

Summary

Introduction

Frontotemporal lobar degeneration (FTLD) is a broad term used to describe the major pathology underlying a clinically heterogeneous group of neurodegenerative diseases characterised by progressive changes in executive function, behaviour and/or language. FTLD is typically identified by significant atrophy of the frontal and temporal cortices of the brain, while microscopically, the disease is characterised by the presence of abnormal intracellular protein aggregates. FTLD can be pathologically sub-divided into three major groups based. The FTLD-FUS group encompasses three pathological diagnoses; neurofilament inclusion body disease (NIFID), basophilic inclusion body disease (BIBD) and atypical frontotemporal lobar degeneration with ubiquitinated inclusions (aFTLD-U), collectively accounting for approximately 5–10% of all FTLD cases [27, 33, 39, 41, 42, 55]. A commonality among all three is the presence of pathological inclusions containing the FUS protein

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