Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy.
Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy.
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DOI：
10.1021/acschemneuro.2c00100
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发表时间：
2022-05-18
影响因子：
5
通讯作者：
Pockes, Steffen
中科院分区：
文献类型：
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作者：
Singh, Gurpreet;Liu, Peng;Yao, Katherine R.;Strasser, Jessica M.;Hlynialuk, Chris;Leinonen-Wright, Kailee;Teravskis, Peter J.;Choquette, Jessica M.;Ikramuddin, Junaid;Bresinsky, Merlin;Nelson, Kathryn M.;Liao, Dezhi;Ashe, Karen H.;Walters, Michael A.;Pockes, Steffen
树突棘中神经元蛋白tau的过度积累导致兴奋性神经传递严重减少，从而介导突触和认知缺陷，这是在包括阿尔茨海默病、路易体痴呆、额颞叶痴呆和创伤性脑损伤在内的tau病模型中反复发现的一种基本机制。突触如此受损可能会导致痴呆，这是老年人身体衰弱最可怕的原因之一，目前还没有修复它们的治疗方法。Caspase-2 （Casp2）是这一病理级联的重要组成部分。虽然人们认为Casp2通过水解天冬氨酸314位点的tau蛋白，形成Δtau314发挥作用，但也有可能涉及非催化机制，因为催化死亡的Casp2至少在一种相关的细胞途径中具有生物活性，即自噬。为了解释Casp2对突触功能的病理影响是由于其催化性还是非催化性，我们发现并鉴定了一种新的Casp2抑制剂化合物1 (pKi (Casp2) = 8.12)，它对Casp3的选择性为123倍，对Casp1、Casp6、Casp7和Casp9的选择性为>2000倍。在一项基于casp2介导的tau蛋白裂解的体外实验中，化合物1阻断了Δtau314的产生。重要的是，化合物1阻止了tau在树突棘中的过度积累，并挽救了表达与FTDP-17（一种家族性tau病）相关的P301S tau变体的培养大鼠海马神经元的兴奋性神经传递。这些结果支持进一步开发小分子Casp2抑制剂来治疗tau病中的突触缺陷。
Synaptic and cognitive deficits mediated by a severe reduction in excitatory neurotransmission caused by a disproportionate accumulation of the neuronal protein tau in dendritic spines is a fundamental mechanism that has been found repeatedly in models of tauopathies, including Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, and traumatic brain injury. Synapses thus damaged may contribute to dementia, among the most feared cause of debilitation in the elderly, and currently there are no treatments to repair them. Caspase-2 (Casp2) is an essential component of this pathological cascade. Although it is believed that Casp2 exerts its effects by hydrolyzing tau at aspartate-314, forming Δtau314, it is also possible that a non-catalytic mechanism is involved, since catalytically dead Casp2 is biologically active in at least one relevant cellular pathway, i.e., autophagy. To decipher whether the pathological effects of Casp2 on synaptic function are due to its catalytic or non-catalytic properties, we discovered and characterized a new Casp2 inhibitor, compound 1 (pKi (Casp2) = 8.12), which is 123-fold selective versus Casp3 and >2000-fold selective versus Casp1, Casp6, Casp7, and Casp9. In an in vitro assay based on Casp2-mediated cleavage of tau, compound 1 blocked the production of Δtau314. Importantly, compound 1 prevented tau from accumulating excessively in dendritic spines and rescued excitatory neurotransmission in cultured primary rat hippocampal neurons expressing the P301S tau variant linked to FTDP-17, a familial tauopathy. These results support the further development of small molecule Casp2 inhibitors to treat synaptic deficits in tauopathies.
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DOI：
10.1098/rstb.2013.0144
发表时间：
2014-01-05
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Kimura T;Whitcomb DJ;Jo J;Regan P;Piers T;Heo S;Brown C;Hashikawa T;Murayama M;Seok H;Sotiropoulos I;Kim E;Collingridge GL;Takashima A;Cho K
通讯作者：
Cho K
影响因子：
15.1
作者：
Carroll JB;Southwell AL;Graham RK;Lerch JP;Ehrnhoefer DE;Cao LP;Zhang WN;Deng Y;Bissada N;Henkelman RM;Hayden MR
通讯作者：
Hayden MR
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
5.3
作者：
Teravskis, Peter J.;Covelo, Ana;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
4.2
作者：
Metcalf, Brian;Chuang, Chihyuan;Li, Zhe
通讯作者：
Li, Zhe