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

Authors

Lauren M. Gittings, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
Sandrine C. Foti, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
Bridget C. Benson, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
Priya Gami-Patel, Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK.
Adrian M. Isaacs, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.
Tammaryn Lashley, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK. t.lashley@ucl.ac.uk.

Document Type

Article

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.

Keywords

FTLD, FUS, Frontotemporal lobar degeneration, Heterogeneous nuclear ribonucleoprotein, hnRNP Q, hnRNP R

Medical Subject Headings

Adult; Aged; Aged, 80 and over; Female; Frontotemporal Lobar Degeneration (metabolism, pathology); Heterogeneous-Nuclear Ribonucleoproteins (metabolism); Hippocampus (metabolism, pathology); Humans; Inclusion Bodies (metabolism, pathology); Intranuclear Inclusion Bodies (metabolism, pathology); Male; Middle Aged; RNA-Binding Protein FUS (metabolism); Temporal Lobe (metabolism, pathology)

Publication Date

2-12-2019

Publication Title

Acta neuropathologica communications

E-ISSN

2051-5960

Volume

7

Issue

1

First Page

18

PubMed ID

30755280

Digital Object Identifier (DOI)

10.1186/s40478-019-0673-y

Recommended Citation

Gittings, Lauren M.; Foti, Sandrine C.; Benson, Bridget C.; Gami-Patel, Priya; Isaacs, Adrian M.; and Lashley, Tammaryn, "Heterogeneous nuclear ribonucleoproteins R and Q accumulate in pathological inclusions in FTLD-FUS" (2019). Translational Neuroscience. 2310.
https://scholar.barrowneuro.org/neurobiology/2310