Pathological role of c-Abl in alpha-synucleinoapathy

描述（由申请人提供）：PD是一种累及多种神经元群的进行性神经退行性疾病。除了对症治疗，没有办法阻止帕金森病潜在神经变性的进展。不幸的是，除了对症治疗，没有办法阻止帕金森病潜在神经变性的进展。目前，α-突触核蛋白（αS）异常被认为是PD及其他α-突触核蛋白病相关疾病的重要致病因子。因此，了解αS异常如何发生并导致大脑神经退行性变对于PD疾病修饰疗法的发展至关重要。为了了解α-突触核蛋白病是如何导致神经退行性疾病的，我们正在研究一种转基因（Tg）小鼠模型，其中A53T突变体人αS （HuαS）的表达导致成人发病的致死性神经退行性疾病。小鼠表现出人α-突触核蛋白病的许多特征，包括αS聚集和多个神经元群的神经变性。我们的研究表明，应激激活的激酶c-Abl在hua α s (A53T) Tg小鼠中被激活。我们认为c-Abl的激活通过激活p53和抑制自噬参与PD的神经退行性变。具体来说，我们提出c-Abl的激活导致mdm2的抑制和细胞质p53的异常激活。值得注意的是，除了p53促进细胞凋亡的作用外，p53代谢异常还可以抑制自噬。因此，c-Abl抑制剂可用于减轻αS病理引起的进行性神经退行性变。鉴于多种神经退行性疾病的治疗意义，我们提出以下目标，以充分确定c-Abl激活在α-突触核蛋白病中的作用。1)用c-Abl敲除小鼠确定α-突触核蛋白病中c-Al的病理特异性；2)确定mdm2/p53通路是否参与α-突触核蛋白病变及自噬调节；3)确定IRE1α和mTOR功能在c-Abl/p53调控自噬中的作用。通过使用遗传模型，所提出的研究结果将为c-Abl作为PD和其他α-突触核蛋白病的治疗靶点提供明确的测试。此外，我们的研究结果将提供体内c-Abl、p53、自噬和α-突触核蛋白病之间的一种新的机制联系。

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.