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

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-019-0673-y) contains supplementary material, which is available to authorized users.

Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome

“…In addition, the functional families of proteins found enriched in inclusions are similar to what has been seen in other types of inclusions. RNA binding proteins, and especially hnRNPs, have previously been detected in other types of inclusion disorders, as well as chaperones, particularly heat shock proteins [21, 24, 34, 65, 92, 111]. The presence of proteasomal proteins in FXTAS inclusions is not surprising as a connection between the UPS and inclusions has long been suspected.…”

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

“…These diseases now fall under the umbrella term of FTLD-FUS which represents about 5–10% of ubiquitin-positive FTLDs [ 107 ]. Several hnRNPs including hnRNP A1, R and Q have been identified to co-deposit with a proportion of FUS-positive pathological inclusions [ 58 , 63 ]. Interestingly, multiple other hnRNPs (D, L and I) were also found within FUS-negative FTLD-FUS inclusions, supporting a wider role of RBP dysregulation beyond FUS-induced pathobiology [ 58 ].…”

“…Interestingly, sporadic ALS cases displayed a more nuclear localisation of hnRNP Q whilst C9-ALS cases showed more diffuse cytoplasmic immunoreactivity; although the reason for this disparity remains unknown [ 9 ]. Additionally, in FTLD hnRNP R mRNA expression was found to be significantly increased and a pathological assessment revealed both hnRNP R and Q proteins to be present in neuronal cytoplasmic inclusions and occasional nuclear inclusions within FTLD-FUS cases [ 63 ]. Double immunofluorescence with FUS and its nuclear transporter Transportin confirmed colocalisation between hnRNP R and the FUS protein in these cases.…”

Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases

“…3). hnRNPs R and Q have also been found to co-deposit with FUS in FTLD-FUS inclusions [153], suggesting that impaired nucleocytoplasmic transport may contribute to disease pathology (Fig. 3).…”