HnRNP K mislocalisation in neurons of the dentate nucleus is a novel neuropathological feature of neurodegenerative disease and ageing

Abstract

Nuclear depletion and cytoplasmic mislocalisation of the RNA-binding protein heterogeneous ribonucleoprotein K (hnRNP K) within pyramidal neurons of the frontal cortex have been shown to be a common neuropathological feature in frontotemporal lobar degeneration (FTLD) and elderly control brain. Here, we describe a second neuronal subtype vulnerable to mislocalisation within the dentate nucleus of the cerebellum. In contrast to neurons within the cerebellar cortex that typically exhibited normal, nuclear staining, many neurons of the dentate nucleus exhibited striking mislocalisation of hnRNP K to the cytoplasm within neurodegenerative disease brain. Mislocalisation frequency in this region was found to be significantly higher in both FTLD-TDP A and Alzheimer's disease (AD) brain than in age-matched controls. However, within control (but not disease) subjects, mislocalisation frequency was significantly associated with age-at-death with more elderly controls typically exhibiting greater levels of the pathology. This study provides further evidence for hnRNP K mislocalisation being a more anatomically diverse pathology than previously thought and suggests that potential dysfunction of the protein may be more broadly relevant to the fields of neurodegeneration and ageing.

Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles

“…BACE1 levels were higher than controls (table 1), but unlike subtypes 1 and 2, abeta40 levels were similar to controls, suggesting a different mechanism associated with higher BACE1 levels for this subtype. Proteins specifically increased in subtype 3 included heterogenous nuclear ribonucleoproteins (hnRNPs) 70 and other RNA binding proteins, which may point to RNA dysregulation. HNRNPs, are involved in maturation of pre-mRNAs, mRNA stabilisation during transport and local mRNA translation for many RNAs, including those important for cytoskeleton organisation 71,72 .…”

“…Disruptions in HnRNPs and mRNA have been associated with tau tangles in previous proteomic studies 73 . Mislocalised hnRNPs could lead to mis-and/or cryptic splicing, resulting in dysfunctional proteins 70,74 . For example, cryptic splicing of STMN2 is a hallmark of TDP43 mislocalisation 75 , resulting in shorter proteins and decreased STMN2 levels in tissue 76 .…”

Gene Self-Expressive Networks as a Generalization-Aware Tool to Model Gene Regulatory Networks

“…Interestingly, in both sub-GRNs, the number of TGs that each TF controls varies to an important degree, exhibiting a scale-free like topology. The analysis of the top-10 TFs controlling the highest number of TGs, has revealed that most of these TFs have been found associated to Alzheimer disease in previous studies [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ], as reported in Table 4 . The full lists of TFs belonging to both communities are reported in Table A1 .…”

An arrayed genome‐wide perturbation screen identifies the ribonucleoprotein Hnrnpk as rate‐limiting for prion propagation

“…We put efforts forth in investigating Hnrnpk as a prion modulator, due to its strong effect size, ubiquitous expression (Uhlén et al , 2015 ), and its recent implications in several protein misfolding diseases (Moujalled et al , 2015 ; Bampton et al , 2021 ; Sidhu et al , 2022 ). As Hnrnpk is a cell‐essential gene (Tsherniak et al , 2017 ), we followed several lines of validation in human and mouse cells as well as different modes of genetic perturbation.…”