Pathological role of c-Abl in alpha-synucleinoapathy

c-Abl 在 α-突触核蛋白淡漠中的病理作用

• 批准号: 9120184
• 负责人: MICHAEL K LEE
• 金额: $ 44.11万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120184
• 关键词: ABL1 gene; Adult; Affect; Aftercare; Animal Model; Apoptosis; Attenuated; Autophagocytosis; Brain; Cell Death; Cells; DDR1 gene; DDR2 gene; Defect; Development; Disease; Event; Exhibits; FDA approved; FRAP1 gene; Future; Gene Targeting; Genes; Genetic Models; Human; Knockout Mice; Lead; Link; Mediating; Metabolism; Modeling; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; PDGFRB gene; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Population; Protein Tyrosine Kinase; Regulation; Role; Signal Transduction; Specificity; Stress; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Transgenic Mice; Treatment Efficacy; alpha synuclein; c-abl Proto-Oncogenes; effective therapy; genetic approach; in vivo; information model; inhibition of autophagy; inhibitor/antagonist; mTOR inhibition; mouse model; mutant; neurotoxic; new therapeutic target; novel; parkin gene/protein; prevent; progressive neurodegeneration; public health relevance; synuclein; synucleinopathy; targeted treatment; therapeutic target; therapy development; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): PD is a progressive neurodegenerative disease involving a variety of neuronal population. Other then symptomatic therapies, there are no ways to stop the progression of underlying neurodegeneration in PD. Unfortunately, other then symptomatic therapies, there are no ways to stop the progression of underlying neurodegeneration in PD. Currently, abnormalities in α-synuclein (αS) is considered as a critical pathogenic agent in PD and other related diseases classified as α-synucleinopathies. Thus, understanding how αS abnormalities occur and cause neurodegeneration in brain appears critical for development of disease modifying therapies for PD. To understand the how α-synucleinopathy leads to neurodegeneration, we are studying a transgenic (Tg) mouse model where the expression of the A53T mutant human αS (HuαS) leads to adult-onset fatal neurodegenerative disease. The affected mice exhibit many features of human α-synucleinopathies, including αS aggregation and neurodegeneration of multiple neuronal population. Our studies show that a stress activated kinase, c-Abl, is activated with the disease in the HuαS(A53T) Tg mice. We propose that activation of c-Abl contributes to neurodegeneration in PD by activation of p53 and inhibition of autophagy. Specifically, we propose that c-Abl activation leads to inhibition of mdm2 and abnormal activation of cytosolic p53. Significantly, in addition to the established role of p53 in promoting apoptosis, abnormal metabolism of p53 can also inhibit autophagy. Thus, inhibitors of c-Abl may be used to attenuate the progressive neurodegeneration caused by αS pathology. Given the therapeutic implications for multiple neurodegenerative diseases, we propose following aims to fully define the role of c-Abl activation in α-synucleinopathy. 1) Determine the pathologic specificity of c-Al in α-synucleinopathy using c-Abl knockout mice; 2) Determine whether mdm2/p53 pathway is involved in α-synucleinopathy and regulation of autophagy; and 3) Determine the role of IRE1α and mTOR function in the regulation of autophagy by c-Abl/p53. By using genetic models, results of the proposed studies will provide unambiguous test of c-Abl as a therapeutic target for PD and other α-synucleinopathies. Further, our results will provide a novel mechanistic link between c-Abl, p53, autophagy, and α-synucleinopathy in vivo.

描述（由申请方提供）：PD是一种进行性神经退行性疾病，涉及多种神经元群体。除对症治疗外，没有任何方法可以阻止PD中潜在神经退行性疾病的进展。不幸的是，其他对症治疗方法无法阻止PD中潜在神经变性的进展。目前，α-突触核蛋白（αS）的异常被认为是PD和其他归类为α-突触核蛋白病的相关疾病的关键致病因子。因此，了解αS异常如何发生并导致脑神经退行性变对于开发PD的疾病改善疗法至关重要。为了了解α-突触核蛋白病如何导致神经变性，我们正在研究一种转基因（Tg）小鼠模型，其中A53 T突变型人αS（HuαS）的表达导致成人发病的致命性神经变性疾病。受影响的小鼠表现出许多人类α-突触核蛋白病的特征，包括αS聚集和多个神经元群体的神经变性。我们的研究表明，在HuαS（A53 T）Tg小鼠中，应激激活的激酶c-Abl在疾病中被激活。我们认为c-Abl的激活通过激活p53和抑制自噬而促进PD的神经变性。具体而言，我们建议，c-Abl激活导致mdm 2的抑制和胞质p53的异常激活。值得注意的是，除了p53在促进细胞凋亡中的既定作用外，p53的异常代谢也可以抑制自噬。因此，c-Abl的抑制剂可用于减轻由αS病理引起的进行性神经变性。考虑到对多种神经退行性疾病的治疗意义，我们提出以下目标，以充分定义c-Abl激活在α-突触核蛋白病中的作用。1)使用c-Abl敲除小鼠确定c-Al在α-突触核蛋白病中的病理特异性; 2）确定mdm 2/p53通路是否参与α-突触核蛋白病和自噬的调节; 3）确定IRE 1 α和mTOR功能在c-Abl/p53调节自噬中的作用。通过使用遗传模型，拟议研究的结果将提供c-Abl作为PD和其他α-突触核蛋白病治疗靶点的明确测试。此外，我们的研究结果将提供c-Abl，p53，自噬和体内α-突触核蛋白病之间的新机制联系。