EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes.
EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes.
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DOI：
10.1016/j.isci.2022.104877
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发表时间：
2022-09-16
期刊：
影响因子：
5.8
通讯作者：
Meyer, Kathrin C.
中科院分区：
文献类型：
--
作者：
Dennys, Cassandra;Baggio, Carlo;Rodrigo, Rochelle;Roussel, Florence;Kulinich, Anna;Heintzman, Sarah;Fox, Ashley;Kolb, Stephen J.;Shaw, Pamela J.;Ethell, Iryna M.;Pellecchia, Maurizio;Meyer, Kathrin C.
肌萎缩侧索硬化症（ALS）是一种渐进性破坏运动神经元（MN）的退行性疾病。早期的研究确定EphA 4，一种受体酪氨酸激酶，作为一种可能的疾病修饰基因。运动神经元和星形胶质细胞中EphA 4受体与其肝配蛋白配体之间的复杂相互作用尚未完全阐明，并且包括与肝配蛋白结合的受体相比未结合的受体的推定促凋亡活性。我们最近报道了ALS患者的星形胶质细胞在共培养的MN中诱导细胞死亡。在这里，我们发现第一代合成EphA 4激动剂123 C4在与来自多个亚组（sALS和突变体SOD 1）的ALS患者的反应性星形胶质细胞共培养时有效地保护MN。新一代和更有效的EphA 4激动剂150 D4、150 E8和150 E7在较低的治疗剂量下提供有效的保护。总而言之，数据表明EphA 4激动剂的开发可能为ALS患者提供了一种有希望的治疗策略。我们报告了靶向其配体结合结构域的有效和选择性EphA 4药物我们使用了一种从患者成纤维细胞产生神经元祖细胞的方法该药物逆转运动神经元细胞死亡是ALS患者的细胞模型我们的EphA 4激动剂可以有效地预防星形胶质细胞介导的运动神经元毒性医学生物化学;分子生物学;神经科学
Amyotrophic lateral sclerosis (ALS) is a degenerative disease that progressively destroys motor neurons (MNs). Earlier studies identified EphA4, a receptor tyrosine kinase, as a possible disease-modifying gene. The complex interplay between the EphA4 receptor and its ephrin ligands in motor neurons and astrocytes has not yet been fully elucidated and includes a putative pro-apoptotic activity of the unbound receptor compared to ephrin-bound receptor. We recently reported that astrocytes from patients with ALS induce cell death in co-cultured MNs. Here we found that first-generation synthetic EphA4 agonistic agent 123C4, effectively protected MNs when co-cultured with reactive astrocytes from patients with ALS from multiple subgroups (sALS and mutant SOD1). Newer generation and more potent EphA4 agonistic agents 150D4, 150E8, and 150E7 provided effective protection at a lower therapeutic dose. Combined, the data suggest that the development of EphA4 agonistic agents provides potentially a promising therapeutic strategy for patients with ALS. We report on potent and selective EphA4 agents targeting its ligand-binding domain We used a method that generates neuronal progenitor cells from patient fibroblasts The agents reverse motor neuron cell death are cellular models of patients with ALS Our EphA4 agonists can effectively prevent astrocyte-mediated motor neuron toxicity Medical biochemistry; Molecular biology; Neuroscience
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影响因子：
7.3
作者：
Baggio C;Kulinich A;Dennys CN;Rodrigo R;Meyer K;Ethell I;Pellecchia M
通讯作者：
Pellecchia M
影响因子：
7.8
作者：
Gatto N;Dos Santos Souza C;Shaw AC;Bell SM;Myszczynska MA;Powers S;Meyer K;Castelli LM;Karyka E;Mortiboys H;Azzouz M;Hautbergue GM;Márkus NM;Shaw PJ;Ferraiuolo L
通讯作者：
Ferraiuolo L
影响因子：
4
作者：
Baggio, Carlo;Udompholkul, Parima;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio
影响因子：
3
作者：
Sreedharan, J.
通讯作者：
Sreedharan, J.
影响因子：
7.1
作者：
Rue, Laura;Oeckl, Patrick;Lemmens, Robin
通讯作者：
Lemmens, Robin