Calpain-mediated tau fragmentation is altered in Alzheimer's disease progression.
Calpain-mediated tau fragmentation is altered in Alzheimer's disease progression.
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DOI：
10.1038/s41598-018-35130-y
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发表时间：
2018-11-13
影响因子：
4.6
通讯作者：
van der Brug MP
中科院分区：
文献类型：
--
作者：
Chen HH;Liu P;Auger P;Lee SH;Adolfsson O;Rey-Bellet L;Lafrance-Vanasse J;Friedman BA;Pihlgren M;Muhs A;Pfeifer A;Ernst J;Ayalon G;Wildsmith KR;Beach TG;van der Brug MP
细胞内 tau 蛋白的聚集是阿尔茨海默病 (AD) 的一个主要标志。 AD 大脑中 tau 蛋白病理学的范围和典型传播与疾病进展期间的认知能力下降相关。在这里，我们对一组特征明确的 AD 和年龄匹配的对照受试者中的内源性 tau 碎片进行了深入分析。使用蛋白质质谱和 Edman 降解来检测人脑中的内源性 tau 片段，我们确定了两个新的蛋白水解位点 G323 和 G326，它们是正常和 AD 皮质中主要的 tau 裂解事件。这些位点位于最近确定为 tau 原丝结构核心的序列内，表明原纤维形成的抑制机制。相比之下，一组不同的新裂解显示出 AD 晚期的明显增加。这些疾病相关位点位于原丝核心序列之外。我们证明钙蛋白酶 1 在体外可以在正常和患病位点特异性切割，并且位点选择具有构象依赖性。单体 tau 主要在 G323/G326（正常位点）处裂解，而寡聚化会增加晚期 AD 相关位点的裂解。疾病和健康状态特有的碎片模式表明人脑中 tau 蛋白聚集的新调控机制。
The aggregation of intracellular tau protein is a major hallmark of Alzheimer’s disease (AD). The extent and the stereotypical spread of tau pathology in the AD brain are correlated with cognitive decline during disease progression. Here we present an in-depth analysis of endogenous tau fragmentation in a well-characterized cohort of AD and age-matched control subjects. Using protein mass spectrometry and Edman degradation to interrogate endogenous tau fragments in the human brain, we identified two novel proteolytic sites, G323 and G326, as major tau cleavage events in both normal and AD cortex. These sites are located within the sequence recently identified as the structural core of tau protofilaments, suggesting an inhibitory mechanism of fibril formation. In contrast, a different set of novel cleavages showed a distinct increase in late stage AD. These disease-associated sites are located outside of the protofilament core sequence. We demonstrate that calpain 1 specifically cleaves at both the normal and diseased sites in vitro, and the site selection is conformation-dependent. Monomeric tau is predominantly cleaved at G323/G326 (normal sites), whereas oligomerization increases cleavages at the late-AD-associated sites. The fragmentation patterns specific to disease and healthy states suggest novel regulatory mechanisms of tau aggregation in the human brain.
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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：
15
作者：
Daebel, Venita;Chinnathambi, Subashchandrabose;Lange, Adam
通讯作者：
Lange, Adam
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
4
作者：
Dronse, Julian;Fliessbach, Klaus;Drzezga, Alexander
通讯作者：
Drzezga, Alexander
DOI：
10.1016/0006-291x(89)91150-9
发表时间：
1989-09-29
影响因子：
3.1
作者：
JOHNSON, GVW;JOPE, RS;BINDER, LI
通讯作者：
BINDER, LI