Tau and saitohin gene expression pattern in progressive supranuclear palsy

Abstract

Deregulation of tau mRNA splicing may contribute to causing progressive supranuclear palsy (PSP). The inclusion of exon 10 produces tau protein isoforms containing all four microtubule-binding repeats (4R). Its exclusion gives rise to isoforms with three microtubule-binding repeats (3R). Alternative splicing of exons 2 and 3 produces the 0N, 1N or 2N protein isoforms. Saitohin (STH) is a nested gene included in intron 9 of tau. It has an unknown function, but could also be involved in the pathological process associated with PSP. We used real-time PCR to investigate the level of expression of tau mRNA isoforms and STH mRNA in the frontal cortex and globus pallidus of PSP patients' brains. mRNA levels were compared with those in the brains of two controls groups: healthy controls and Alzheimer's disease patients (AD). The 4R/3R mRNA ratio was significantly higher in the globus pallidus of PSP patients than in controls. The 0N mRNA isoform levels were statistically higher in the frontal cortex and globus pallidus of AD patients and were borderline higher in the globus pallidus of PSP patients than controls. In addition, when all samples were taken into account (PSP + AD + controls), a significant correlation was found between the 4R/3R mRNA tau ratio and STH expression. This correlation was stronger in the globus pallidus than in the frontal cortex. Our results suggest that abnormalities in the alternative splicing of the tau gene are involved in the molecular mechanism related to PSP pathogenesis. Such abnormalities cause an increase in the 4R/3R ratio and may lead to an overexpression of 0N tau isoforms.