Brain tau isoform mRNA and protein correlation in PSP brain

Abstract

Abstract Insoluble aggregates of the microtubule associated protein, tau are pathological hallmarks of several neurodegenerative diseases, including Alzheimer’s disease (AD), called tauopathies. The tau gene (MAPT) is alternatively spliced and the composition of resulting protein isoforms in aggregates is disease specific. Progressive supranuclear palsy (PSP) is characterised by tangles predominantly containing isoforms with four microtubule binding repeat domains (4R-tau) suggesting that changes in isoform-specific mRNA expression play a role the pathogenesis of the disease. This is supported by the genetics of MAPT. In this study, we quantified expression of 3R- and 4R-tau isoforms at both the mRNA and protein levels in the caudate nucleus, a region severely affected by tau pathology. Results from real-time qPCR and a recently developed ELISA showed statistically significant increase in 4R-tau isoforms in PSP samples compared to controls. In addition, we measured soluble and insoluble hyperphosphorylated tau protein fractions in each PSP sample and compared to the corresponding mRNA transcript levels. No strong correlations were observed with either 3R- or 4R-tau. These findings confirmed the increased ratio of 4R-tau:3R-tau isoforms in PSP. However, we did not find a direct quantitative relationship between individual mRNA and protein levels suggesting a more complex regulation of isoform expression at the post-transcriptional level.