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

Neuroscience. 2023 May 10:518:54-63. doi: 10.1016/j.neuroscience.2022.07.014. Epub 2022 Jul 19.


Huntington's 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 protein 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 neurodegeneration. 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 samples from HD (N = 48) and healthy control (N = 25) subjects. We first show that levels of 4R-tau (exon 10 inclusion) 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.

Keywords: Cortex; Huntington’s disease; Neurodegeneration; Putamen; Splicing; Tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Brain / metabolism
  • Exons
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease* / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • tau Proteins* / genetics
  • tau Proteins* / metabolism


  • tau Proteins
  • Protein Isoforms
  • Huntingtin Protein