Characterizing the expression profile of 3R tau pathology in Pick's disease.

Abstract

Pick's disease (PiD) is a rare neurodegenerative disorder defined by dementia, frontotemporal lobe atrophy, and 3-repeat tau inclusions. To elucidate PiD pathobiology, we performed the first bulk transcriptomics study on PiD using short- and long-read sequencing on the parietal cortex of 28 PiD and 15 control samples. We identified several significantly differentially expressed genes, with <i>CCL2</i> displaying the strongest association with 3-repeat tau pathology and increased burden in PiD compared to those in 4-repeat tau progressive supranuclear palsy (PSP) cases. Investigation of co-expressed genes and pathways suggested the involvement of mRNA processing, mitochondrial function, and immune processes in disease pathobiology. Long-read RNA sequencing on a subset of samples (eight PiD and four control) proposed novel, potentially disease-associated transcripts for <i>AZGP1</i>, <i>CD44</i>, <i>HSD11B2</i>, and <i>WIF1</i>, predicted to result in truncated proteins. In conclusion, we observed transcriptomic changes in the parietal cortex of patients with PiD that may inform into clinically relevant biomarkers and therapeutic strategies.