基础科学和病原发生学
Thor D Stein1,2,3, Nurgul Aytan4, Jenny A Empawi5
1Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Alzheimer's & dementia : the journal of the Alzheimer's Association
|December 23, 2025
概括
与慢性创伤性脑病变 (CTE) 相关的重复头部冲击可能会通过TDP-43病理导致认知衰退,导致基因错误拼接和EPB41L1和RAP1GAP的蛋白质水平降低.
科学领域:
- 神经科学是一个神经科学.
- 神经病理学神经病理学
- 遗传学 是一个遗传学.
背景情况:
- 重复的头部冲击与TDP-43病理有关,特别是在海马和额叶皮质,这是慢性创伤性脑病变 (CTE) 的标志.
- 在CTE中TDP-43的含有与严重的认知障碍相关,但潜在的机制尚不清楚.
- 在其他神经退行性疾病 (如ALS和FTLD-TDP) 中,TDP-43病理与基因错误拼接和神秘的外显子表达有关.
研究的目的:
- 调查CTE中TDP-43病理是否有助于基因错误拼接,选择性蛋白质损失和随后的神经退行.
- 为了确定受误组合和CTE中蛋白质减少影响的特定基因,并包括TDP-43.
- 探索这些分子变化与CTE认知障碍之间的关联.
主要方法:
- 对212名脑捐赠者进行了检查,他们有CTE和TDP-43包括在内的重复头部撞击史.
- 在背侧前额皮质上进行了大量RNA测序和蛋白质组学.
- 使用LeafCutter在CTE病例中分析了使用LeafCutter分析的变量拼接事件,其中包括 (CTE-TDP) 和没有TDP-43在海马体或额叶皮层的入.
主要成果:
- 51%的CTE病例 (72/142) 呈现TDP-43的包括 (CTE-TDP).
- 在CTE-TDP中的836个基因中发现了改变的拼接,与CTE相比 (FDR<0.01),其中23个与ALS/FTLD-TDP重叠.
- 在CTE-TDP中观察到EPB41L1和RAP1GAP的蛋白质水平显著降低,与TDP-43负载相关,并与痴呆症相关.
结论:
- EPB41L1和RAP1GAP对于突触可塑性和信号传递至关重要.
- 基因错误拼接和EPB41L1和RAP1GAP的蛋白质表达减少可能导致TDP-43病理的CTE神经退行和认知缺陷.
- 这些发现阐明了潜在的分子机制,将头部创伤,TDP-43病理和CTE的认知障碍联系起来.
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