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

Autor: Petry S; Centre de recherche du CHU de Québec-Université Laval, CHUL, Axe Neurosciences, Québec, Canada., Nateghi B; Centre de recherche du CHU de Québec-Université Laval, CHUL, Axe Neurosciences, Québec, Canada., Keraudren R; Centre de recherche du CHU de Québec-Université Laval, CHUL, Axe Neurosciences, Québec, Canada., Sergeant N; Inserm, CHU Lille, University of Lille, Lille, France; Alzheimer and Tauopathies, LabEx DISTALZ, Lille France., Planel E; Centre de recherche du CHU de Québec-Université Laval, CHUL, Axe Neurosciences, Québec, Canada; Faculté de médecine, Département de psychiatrie et de neurosciences, Université Laval, Québec, Canada., Hébert SS; Centre de recherche du CHU de Québec-Université Laval, CHUL, Axe Neurosciences, Québec, Canada; Faculté de médecine, Département de psychiatrie et de neurosciences, Université Laval, Québec, Canada. Electronic address: sebastien.hebert@crchudequebec.ulaval.ca., St-Amour I; Centre de recherche du CHU de Québec-Université Laval, CHUL, Axe Neurosciences, Québec, Canada; CERVO Brain Research Centre, Centre Intégré Universitaire de Santé et des Services Sociaux de la Capitale-Nationale, Québec, Canada; Faculté de pharmacie, Université Laval, Québec, Canada. Electronic address: isabelle.st-amour@cervo.ulaval.ca.
Jazyk: angličtina
Zdroj: Neuroscience [Neuroscience] 2023 May 10; Vol. 518, pp. 54-63. Date of Electronic Publication: 2022 Jul 19.
DOI: 10.1016/j.neuroscience.2022.07.014
Abstrakt: 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.
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Databáze: MEDLINE
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