Differential Regulation of Tau Exon 2 and 10 Isoforms in Huntington's Disease Brain

disease (HD) is an inherited neurodegenerative disorder caused by an expansion of CAG repeats in the Huntingtin (HTT) gene. Accumulating evidence suggests that the microtubule-associated tau pro-tein participates in the pathogenesis of HD. Recently, we have identified changes in tau alternative splicing of exons 2, 3 and 10 in the putamen of HD patients (St-Amour et al, 2018). In this study, we sought to determine whether tau mis-splicing events were equally observed in other brain regions that are less prone to neurodegen-eration. Using Western blot and PCR, we characterized the relationship between MAPT splicing of exons 2, 3 and 10, tauopathy and Htt pathologies, as well as neurodegeneration markers in matching putamen and cortical sam -ples from HD (N = 48) and healthy control (N = 25) subjects. We first show that levels of 4R-tau (exon 10 inclu-sion) isoforms are higher in both the putamen and the cortex of individuals with HD, consistent with earlier findings. On the other hand, higher 0N-tau (exclusion of exons 2 and 3) and lower 1N-tau (exclusion of exon 3) isoforms were seen exclusively in the putamen of HD individuals. Interestingly, investigated splicing factors were deregulated in both regions whereas exon 2 differences coincided with increased tau hyperphosphorylation, aggregation and markers of neurodegeneration. Overall, these results imply a differential regulation of tau exon 2 and exon 10 alternative splicing in HD putamen that could provide a useful biomarker or therapeutic target. This article is part of a Special Issue entitled: SI: The Molecular Bases of Tauopathies. (c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

This study investigates the alternative splicing of tau protein in HD patients and identifies abnormal splicing events in the putamen. Differences in exon 2 splicing coincide with increased tau hyperphosphorylation, aggregation, and markers of neurodegeneration, suggesting a potential biomarker or therapeutic target.