Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity.
Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity.
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DOI：
10.1002/mds.28858
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Olanow CW
中科院分区：
文献类型：
--
作者：
Werner MH;Olanow CW
帕金森氏病(PD)是第二大最常见的中枢神经系统退行性疾病，全世界估计有500万例。帕金森病的历史特征是黑质致密部多巴胺能神经元的进行性丢失，现在已知帕金森病的病理广泛存在，影响到5-羟色胺、胆碱能和去甲肾上腺素神经元以及嗅觉系统、大脑半球、脑干、脊髓和外周自主神经系统的神经细胞。帕金森病的病理特征是错误折叠的α-突触核蛋白的积聚，这被认为在疾病的发病机制中发挥了关键作用。帕金森病的动物模型表明，Abelson酪氨酸激酶(c-Abl)的激活在α-突触核蛋白病理和神经退行性变的发生和发展中起着重要作用。这些研究表明，错误折叠的α-突触核蛋白的内化激活了c-Abl，c-Abl使α-突触核蛋白磷酸化，并促进了受影响神经元内的α-突触核蛋白病理。此外，c-Abl使Parkin失活，扰乱线粒体质量控制和生物发生，促进神经退化。对帕金森病患者的尸检研究表明，酪氨酸磷酸化的α-突触核蛋白水平增加，与人类疾病中c-Abl的激活一致。尽管c-Abl抑制剂尼洛替尼在两个双盲试验中未能显示出临床益处，但已经开发出在大脑中积聚的新型c-Abl抑制剂，并可能在饱和水平上抑制c-Abl。这些新的抑制剂已经在帕金森病的动物模型中证明了益处，现在已经进入临床开发。在这里，我们回顾了c-Abl在神经退行性疾病过程中的作用，并考虑了c-Abl抑制剂从模型研究到帕金森病疾病修饰疗法的翻译潜力。©2021 Inhibikase Treateutics，Inc.运动障碍，由Wiley Peribals LLC代表国际帕金森运动障碍协会出版。由于氧化/亚硝化应激、蛋白质突变、清除障碍和/或遗传因素，黑质中出现错误折叠的α-突触核蛋白，导致错误折叠的α-突触核蛋白内化，激活非受体Abelson酪氨酸激酶(c-Abl)，这是帕金森病神经退行性变发生和发展的关键事件。C-Abl的激活既可以使泛素E3连接酶蛋白失活，又可以在受影响的神经元内部产生病理形式的α-突触核蛋白，这两种情况都是在c-Abl特异性酪氨酸磷酸化之后发生的。C-Abl抑制剂的治疗逆转了这些过程，重新激活了Parkin，并通过溶酶体和/或蛋白酶体过程驱动错误折叠和病理性的α-突触核蛋白的清除。在模型系统中，这些事件导致大脑和胃肠道(GI)功能的实质性恢复。尽管c-Abl抑制剂的初步临床试验失败了，但新的c-Abl抑制剂被认为在大脑中积聚的浓度足以阻断c-Abl，现在正在进行临床测试，并提供了评估c-Abl抑制作为PD患者疾病修饰疗法的潜力的机会。1月信息图：通过抑制Abl激酶改变帕金森病：一个机会
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5 000 000 cases worldwide. Historically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, PD pathology is now known to be widespread and to affect serotonin, cholinergic and norepinephrine neurons as well as nerve cells in the olfactory system, cerebral hemisphere, brain stem, spinal cord, and peripheral autonomic nervous system. PD pathology is characterized by the accumulation of misfolded α‐synuclein, which is thought to play a critical role in the etiopathogenesis of the disease. Animal models of PD suggest that activation of the Abelson tyrosine kinase (c‐Abl) plays an essential role in the initiation and progression of α‐synuclein pathology and neurodegeneration. These studies demonstrate that internalization of misfolded α‐synuclein activates c‐Abl, which phosphorylates α‐synuclein and promotes α‐synuclein pathology within the affected neurons. Additionally, c‐Abl inactivates parkin, disrupting mitochondrial quality control and biogenesis, promoting neurodegeneration. Post‐mortem studies of PD patients demonstrate increased levels of tyrosine phosphorylated α‐synuclein, consistent with the activation of c‐Abl in human disease. Although the c‐Abl inhibitor nilotinib failed to demonstrate clinical benefit in two double‐blind trials, novel c‐Abl inhibitors have been developed that accumulate in the brain and may inhibit c‐Abl at saturating levels. These novel inhibitors have demonstrated benefits in animal models of PD and have now entered clinical development. Here, we review the role of c‐Abl in the neurodegenerative disease process and consider the translational potential of c‐Abl inhibitors from model studies to disease‐modifying therapies for Parkinson's disease. © 2021 Inhibikase Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. The emergence of misfolded α‐synuclein in the substantia nigra as a result of oxidative/nitrosative stress, protein mutation, impaired clearance, and/or genetic factors leads to internalization of misfolded α‐synuclein, which activates the non‐receptor Abelson tyrosine kinase (c‐Abl), a key event in the initiation and progression of neurodegeneration in Parkinson's disease. c‐Abl activation both inactivates the ubiquitin E3 ligase parkin and creates the pathological form of α‐synuclein on the inside of the affected neurons, both events following specific tyrosine phosphorylation by c‐Abl. Treatment with a c‐Abl inhibitor reverses these processes, reactivating parkin and driving clearance of misfolded and pathological α‐synuclein through lysosomal and/or proteasomal processes. In model systems, these events result in substantial functional recovery in the brain and gastrointestinal (GI) tract. Although initial clinical trials of c‐Abl inhibitors failed, novel c‐Abl inhibitors thought to accumulate in the brain at concentrations sufficient to block c‐Abl are now being tested in the clinic and offer the opportunity to evaluate the potential of c‐Abl inhibition as a disease‐modifying therapy for patients with PD. January Infographic : Parkinson's Disease Modification through Abl Kinase Inhibition: An Opportunity
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影响因子：
15
作者：
Hejjaoui, Mirva;Butterfield, Sara;Fauvet, Bruno;Vercruysse, Filip;Cui, Jia;Dikiy, Igor;Prudent, Michel;Olschewski, Diana;Zhang, Yan;Eliezer, David;Lashuel, Hilal A.
通讯作者：
Lashuel, Hilal A.
影响因子：
7.3
作者：
Colicelli J
通讯作者：
Colicelli J
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
5.3
作者：
Yamamura Y;Morigaki R;Kasahara J;Yokoyama H;Tanabe A;Okita S;Koizumi H;Nagahiro S;Kaji R;Goto S
通讯作者：
Goto S
影响因子：
168.9
作者：
Ibáñez, P;Bonnet, AM;Brice, A
通讯作者：
Brice, A