Frontotemporal Dementia P301L Mutation Potentiates but Is Not Sufficient to Cause the Formation of Cytotoxic Fibrils of Tau.
Frontotemporal Dementia P301L Mutation Potentiates but Is Not Sufficient to Cause the Formation of Cytotoxic Fibrils of Tau.
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DOI：
10.3390/ijms241914996
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发表时间：
2023-10-08
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
tau蛋白P301L突变是一种与神经退行性额颞叶痴呆（FTD）相关的普遍致病突变。P301L在分子水平上触发或促进神经变性的机制尚不清楚。在这项工作中，我们研究了P301L突变对病理相关的过度磷酸化tau的生化和生物学特性的影响。在体外实验中，过度磷酸化的P301L tau蛋白比过度磷酸化的野生型tau蛋白或未磷酸化的P301L tau蛋白更有效地形成细胞毒性聚集体。机制研究表明，与野生型过度磷酸化的tau治疗相比，过度磷酸化的P301L tau加剧了神经母细胞瘤细胞系中内质网（ER）应激相关基因的上调。此外，微管细胞骨架在过度磷酸化的P301L tau治疗后严重破坏。一种过度磷酸化的tau聚集抑制剂阿波啡也能抑制P301L过度磷酸化tau引起的有害影响。简而言之，tau核心重复结构域内的P301L单突变使潜在的过度磷酸化的tau更有效地引发内质网应激和细胞骨架损伤。然而，单独的P301L突变，没有过度磷酸化，并不足以引起这些表型。了解选择性突变加剧tau致病活性的条件和机制，可以为开发治疗额颞叶痴呆和其他相关神经退行性tau病（包括阿尔茨海默病）的新药物策略提供关键线索。
The P301L mutation in tau protein is a prevalent pathogenic mutation associated with neurodegenerative frontotemporal dementia, FTD. The mechanism by which P301L triggers or facilitates neurodegeneration at the molecular level remains unclear. In this work, we examined the effect of the P301L mutation on the biochemical and biological characteristics of pathologically relevant hyperphosphorylated tau. Hyperphosphorylated P301L tau forms cytotoxic aggregates more efficiently than hyperphosphorylated wildtype tau or unphosphorylated P301L tau in vitro. Mechanistic studies establish that hyperphosphorylated P301L tau exacerbates endoplasmic reticulum (ER) stress-associated gene upregulation in a neuroblastoma cell line when compared to wildtype hyperphosphorylated tau treatment. Furthermore, the microtubule cytoskeleton is severely disrupted following hyperphosphorylated P301L tau treatment. A hyperphosphorylated tau aggregation inhibitor, apomorphine, also inhibits the harmful effects caused by P301L hyperphosphorylated tau. In short, the P301L single mutation within the core repeat domain of tau renders the underlying hyperphosphorylated tau more potent in eliciting ER stress and cytoskeleton damage. However, the P301L mutation alone, without hyperphosphorylation, is not sufficient to cause these phenotypes. Understanding the conditions and mechanisms whereby selective mutations aggravate the pathogenic activities of tau can provide pivotal clues on novel strategies for drug development for frontotemporal dementia and other related neurodegenerative tauopathies, including Alzheimer’s disease.
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DOI：
10.1083/jcb.201007161
发表时间：
2011-02-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gauthier-Kemper A;Weissmann C;Golovyashkina N;Sebö-Lemke Z;Drewes G;Gerke V;Heinisch JJ;Brandt R
通讯作者：
Brandt R
影响因子：
16.2
作者：
Kaufman SK;Sanders DW;Thomas TL;Ruchinskas AJ;Vaquer-Alicea J;Sharma AM;Miller TM;Diamond MI
通讯作者：
Diamond MI
影响因子：
56.9
作者：
Hong, M;Zhukareva, V;Lee, VMY
通讯作者：
Lee, VMY
DOI：
10.1007/978-1-4939-2978-8_7
发表时间：
2016-01-01
期刊：
PROTEIN AMYLOID AGGREGATION: METHODS AND PROTOCOLS
影响因子：
--
作者：
Huseby, Carol J.;Kuret, Jeff
通讯作者：
Kuret, Jeff
影响因子：
4.8
作者：
Guo, Jing L.;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.