Pathological role of c-Abl in alpha-synucleinoapathy

描述(申请人提供)：帕金森病是一种进行性神经退行性疾病，涉及多种神经元群体。除了对症治疗外，没有其他方法可以阻止帕金森病潜在的神经变性的进展。不幸的是，除了对症治疗外，没有其他方法可以阻止帕金森病潜在的神经变性的进展。目前，α-突触核蛋白的异常(αS)被认为是帕金森病和其他相关疾病的关键病原体，被归类为α-突触核病症。因此，了解αS异常是如何发生并导致脑神经变性的似乎对开发帕金森病的疾病修正疗法至关重要。为了了解α-突触核苷酸病是如何导致神经变性的，我们正在研究一个转基因(TG)小鼠模型，在该模型中，A53T突变体人αS(HuαS)的表达会导致成人起病的致命性神经退行性疾病。受影响的小鼠表现出许多人类α-突触核病的特征，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(A53T)Tg小鼠中，应激激活的激酶c-Abl随着疾病的发生而被激活。我们认为c-Abl的激活通过激活P53和抑制自噬参与了帕金森病的神经退变。具体地说，我们认为c-Abl的激活导致MDM2的抑制和胞浆P53的异常激活。值得注意的是，除了P53在促进细胞凋亡方面的既定作用外，P53的异常代谢也可以抑制自噬。因此，c-Abl的抑制剂可能被用来减轻αS病理所致的进行性神经变性。考虑到对多种神经退行性疾病的治疗意义，我们提出以下目标来充分确定c-Abl激活在α-突触核病中的作用。1)利用c-Ab1基因敲除小鼠确定c-Al在α-突触核病中的病理特异性；2)确定mdm2/p53通路是否参与α-突触核病和自噬的调节；3)确定iRE1α和mTOR功能在c-Ab1/p53自噬调节中的作用。通过使用遗传模型，建议的研究结果将为c-Abl作为帕金森病和其他α-突触核病的治疗靶点提供明确的测试。此外，我们的结果将在体内提供c-Abl、p53、自噬和α-突触核素病之间的新的机制联系。

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.