Widespread hnRNP K Mislocalisation Suggests Differential Neuronal Vulnerability in the Neurodegenerative and Ageing Human Brain

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a widely distributed RNA-binding protein in the human brain, playing a crucial role in post-transcriptional regulation, including mRNA metabolism and neuroplasticity. We have previously identified an increase in neuronal hnRNP K mislocalisation in cases of frontotemporal lobar degeneration (FTLD) compared to controls, where loss of nuclear hnRNP K was linked to alternative splicing events. However, the broader distribution of hnRNP K mislocalisation across different brain regions, other diseases and its pathological significance remains unclear. This study systematically examined hnRNP K mislocalisation across 13 brain regions from 19 cases, including different pathological subtypes of FTLD, Parkinson's disease (PD), Alzheimer's disease (AD) and age-matched neurologically normal controls, using immunohistochemistry and quantitative image analysis. The results of the study show that hnRNP K mislocalisation is observed throughout the brain, characterised by nuclear depletion and cytoplasmic aggregation. In the cerebral cortex, mislocalisation was most pronounced in the frontal lobe and least in the occipital lobe, with significant predominance in the depth of sulci compared to gyri. Notably, the basal ganglia, thalamus, medulla and cerebellum exhibited particular vulnerability to hnRNP K pathology. In contrast, Purkinje cells within the cerebellum and CA1-CA2 pyramidal neurons within the hippocampus showed lower levels of mislocalisation. Furthermore, levels of hnRNP K mislocalisation within the putamen correlated significantly with motor symptoms, suggesting a potential link between hnRNP K pathology and motor dysfunction. These findings highlight the propensity of hnRNP K mislocalisation in neurodegenerative diseases and the aged brain and underscore the need for further investigation into its functional consequences.