来自得克萨斯大学圣安东尼奥分校（UT Health San Antonio）今天报道了一种新型机制，通过这种机制，Tau蛋白质的病理形式导致神经元死亡。阿尔茨海默氏病和慢性创伤性脑病（CTE）是包括tau蛋白质病理的20多种疾病。

The newly found mechanism of tau-induced damage can be altered pharmacologically, the scientists noted, making it a novel target for drug development.

该研究发表在阿尔茨海默氏症和痴呆症：阿尔茨海默氏症协会杂志, “provides a framework for future studies in vertebrate models of tauopathy and eventually clinical trials in people,” first author Gabrielle Zuniga said. Zuniga is an MD/PhD student in the South Texas Medical Scientist Training Program offered jointly by the Joe R. and Teresa Lozano Long School of Medicine and the Graduate School of Biomedical Sciences of UT Health San Antonio.

“The fact it is a druggable target is really exciting, and it is a new mechanism that wasn’t previously established,” Zuniga said.

早期事件，在神经元死亡之前

Working with a fruit fly that expresses mutant human tau, the scientists observed deficits in an RNA quality-control pathway known as nonsense-mediated mRNA decay. “This is an early event,” Zuniga said. “These changes in RNA quality control occurred long before neuronal cell death.”

“Nonsense-mediated mRNA decay is a key step in the process by which genetic information is translated into proteins,” Zuniga said. Impairment of this quality-control mechanism results in buildups of RNA and production of abnormal, dysfunctional proteins. “It has an absolutely detrimental effect,” Zuniga said.

DNA（一种称为脱氧核糖核酸的分子）包含蛋白质的遗传蓝图。信使RNA（核糖核酸）读出蓝图以生成蛋白质。当胡说八道介导的mRNA衰减减少时，该信息高速公路将被置于遗迹。

“We are focusing on how cells clear faulty RNAs, and how this RNA quality control mechanism goes awry in disease. If these types of RNAs accumulate in a cell and are translated into proteins, bad things can happen,” said senior author Bess Frost, PhD, Bartell Zachry Distinguished Professor for Research in Neurodegenerative Disorders at UT Health San Antonio. Dr. Frost, associate professor of cell systems and anatomy, is a member of the health science center’s Sam and Ann Barshop Institute for Longevity and Aging Studies and the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases.

Going beyond tau deposition

阿尔茨海默氏病和其他陶氏病的治疗部分失败了，部分原因是它们集中于清除tau蛋白或另一种称为淀粉样蛋白β的蛋白质。淀粉样蛋白β斑块和Tau Tangles是阿尔茨海默氏症的经典标志。

“与其针对疾病过程中后期的tau沉积，为什么不阻止实际导致神经元死亡的途径？”长期医学院神经病学教授，格伦·比格斯学院（Glenn Biggs Institute）的创始董事Sudha Seshadri说。“这似乎是这些途径之一，它的发现是加布里埃尔·祖尼加（Gabrielle Zuniga），弗罗斯特（Frost）和团队的出色侦探作品。”

Seshadri博士和Frost博士是南德克萨斯州阿尔茨海默氏病研究中心的调查员，该研究中心是最近被授予的美国国立卫生研究院卓越研究所，是UT Health San Antonio和UT Rio Grande Valley的合作伙伴关系。它是德克萨斯州唯一指定的阿尔茨海默氏病研究中心。

鉴定tau（和淀粉样蛋白β）病理学的多种机制可能会导致了解哪些患者可能受益于哪些疗法。例如，阿尔茨海默氏病患者的一部分可能对增加胡说八道介导的mRNA衰变的药物有反应。

MD/PhD学生

First author Zuniga completed two years in the Long School of Medicine before embarking on her Doctor of Philosophy studies. She is a June candidate for her PhD degree and will return to medical school in the fall for years three and four of her journey to become a physician. Originally from Chapel Hill, N.C., she is a 2015 graduate of The University of Texas at Austin.

“加布（Gabbe）体现了我们的MSTP学生的光彩，这些学生接受了这一雄心勃勃的双度学术医学路径，并通过进行严格的翻译研究来使生活变得更好，他们决心为人类服务，”医学博士Jose E. Cavazos，博士学位，博士学位，教授，教授神经病学和南德克萨斯医学科学家培训计划（MSTP）的助理院长。

Reference:Zuniga G, Levy S, Ramirez P, et al. Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration.老年痴呆症。dement。2022. doi：10.1002/alz.12653

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