亨廷顿舞蹈病前额叶皮质中丝氨酸396位点tau蛋白磷酸化随年龄增长而增加。

Age-dependent increase in tau phosphorylation at serine 396 in Huntington's disease pre-frontal cortex.

作者信息

Petrozziello Tiziana, Huntress Sommer S, Castillo-Torres Ayleen L, Quinn James P, Connors Theresa R, Auger Corinne A, Mills Alexandra N, Kim Spencer E, Liu Sophia, Mahmood Farah, Boudi Adel, Wu Muzhou, Sapp Ellen, Kivisäkk Pia, Sunderesh Shekar R, Pouladi Mahmoud A, Arnold Steven E, Hyman Bradley T, Rosas H Diana, DiFiglia Marian, Pinto Ricardo Mouro, Kegel-Gleason Kimberly, Sadri-Vakili Ghazaleh

出版信息

medRxiv. 2023 Jun 5:2023.06.03.23290851. doi: 10.1101/2023.06.03.23290851.

DOI:10.1101/2023.06.03.23290851

PMID:37333415

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10274990/

Abstract

BACKGROUND

To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD post-mortem brain and mouse models.

OBJECTIVES

The goal of this study was to determine whether total tau and pTau levels are altered in HD.

METHODS

Immunohistochemistry, cellular fractionations, and western blots were used to measure tau and pTau levels in a large cohort of HD and control post-mortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau in and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay.

RESULTS

Our results revealed that, while there was no difference in tau or pTau levels in HD PFC compared to controls, tau phosphorylated at S396 levels were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, tau or pTau levels were not altered in and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls.

CONCLUSION

Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.

摘要

背景

迄今为止，tau蛋白磷酸化是否在亨廷顿舞蹈病（HD）中起作用仍存在争议，因为先前的研究表明，在HD患者的尸检大脑和小鼠模型中，磷酸化tau（pTau）要么没有变化，要么有所增加。

目的

本研究的目的是确定HD患者中总tau蛋白和pTau水平是否发生改变。

方法

采用免疫组织化学、细胞分级分离和蛋白质印迹法，检测大量HD患者和对照者尸检前额叶皮质（PFC）中的tau蛋白和pTau水平。此外，还进行了蛋白质印迹法，以评估HD患者和对照者同基因胚胎干细胞（ESC）衍生的皮质神经元和神经干细胞（NSC）中的tau蛋白和pTau水平。同样，蛋白质印迹法用于评估和转基因R6/2小鼠中的tau蛋白和pTau。最后，使用Quanterix Simoa分析法评估HD患者和健康对照者血浆中的总tau蛋白水平。

结果

我们的结果显示，虽然与对照组相比，HD患者PFC中的tau蛋白或pTau水平没有差异，但在死亡时年龄在60岁及以上的HD患者的PFC样本中，S396位点磷酸化的tau蛋白水平有所增加。此外，HD患者ESC衍生的皮质神经元和NSC中的tau蛋白和pTau水平没有变化。同样，与野生型同窝小鼠相比，和转基因R6/2小鼠中的tau蛋白或pTau水平没有改变。最后，与对照组相比，一小群HD患者血浆中的tau蛋白水平没有变化。