4.6 Article

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

Journal

ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 7, Issue -, Pages -

Publisher

BMC
DOI: 10.1186/s40478-019-0673-y

Keywords

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

Categories

Funding

  1. Alzheimer's Research UK
  2. Leonard Wolfson Centre for Experimental Neurology
  3. European Research Council (ERC) under the European Union [648716 - C9ND]
  4. Motor Neurone Disease Association
  5. UK Dementia Research Institute
  6. Reta Lila Weston Institute for Neurological Studies
  7. Medical Research Council
  8. MRC [UKDRI-1006] Funding Source: UKRI

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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.

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