Regulation of APP Processing by Par-4

描述（由申请人提供）：我们最近鉴定了亮氨酸拉链蛋白Par-4（前列腺凋亡反应-4）作为与阿尔茨海默病（AD）发病机制相关的新的细胞死亡促进蛋白。重要的是，我们已经发现Par-4可以通过转染的IMR-32细胞中的半胱天冬酶依赖性途径参与调节Abeta产生（Guo Q.例如，Nature Medicine 1998; 4（8）：957-962，Guo Q.例如，J. Biol. Chem.，2001; 276：16040-4）。细胞内钙稳态的破坏可能导致Par-4的异常诱导和β淀粉样前体蛋白（APP）的异常加工。这些数据表明，Par-4可能是APP加工的一种新的调节剂。最近，我们发现Par-4直接与APP相互作用，并改变Abeta分泌。这些数据强烈地表明Par-4通过至少两种不同的机制调节APP加工：（a）通过在凋亡过程中被激活的半胱天冬酶和钙依赖性途径，以及（B）通过与APP的直接物理相互作用。AATF是在神经元中表达的新型亮氨酸拉链蛋白。我们发现AATF直接与Par-4结合并赋予神经保护作用，表明AATF可能是Par-4活性的内源性调节剂。本研究将采用一系列的体内外实验方法来验证以下假设：（1）Par-4在APP的异常加工过程中起重要作用：（2）Par-4通过钙依赖性途径改变APP在凋亡过程中的加工;（3）Par-4直接与APP相互作用，并在凋亡和/或非凋亡条件下改变细胞内A β的产生和/或分泌的APP和A β的细胞外库;（4）AATF是Par-4的一种新的相互作用伙伴，在APP加工过程中起着Par-4活性的内源性负调节剂的作用。拟议的研究可能建立Par-4作为APP加工的新调节剂。通过增强AATF表达和/或操纵Par-4/APP相互作用来抑制Par-4活性可能为阿尔茨海默病提供新的治疗意义。

DESCRIPTION (provided by applicant): We recently identified the leucine zipper protein Par-4 (prostate apoptosis response-4) as a novel cell death promoting protein associated with pathogenesis of Alzheimer's disease (AD). Importantly, we have found that Par-4 may participate in regulation of Abeta production through a caspase-dependent pathway in transfected IMR-32 cells (Guo Q. et al., Nature Medicine 1998; 4(8): 957-962, Guo Q. et al., J. Biol. Chem., 2001; 276: 16040-4). Disruption of intracellular calcium homeostasis may lead to aberrant induction of Par-4 and abnormal processing of beta amyloid precursor protein (APP). These data suggest that Par-4 may be a novel regulator of APP processing. Most recently, we found that Par-4 interacts directly with APP, and alter Abeta secretion. These data strongly indicate that Par-4 regulates APP processing by at least two different mechanisms: (a) by caspase- and calcium-dependent pathways that is activated during apoptotic process, and (b) through direct physical interaction with APP. AATF is a novel leucine zipper protein that is expressed in neurons. We found AATF binds directly to Par-4 and confers neuroprotective actions, indicating that AATF might be an endogenous regulator of Par-4 activity. The proposed studies will employ a series of in vitro and in vivo approaches to test the following hypotheses: (1) Par-4 plays an essential role in aberrant APP processing of APP after initiation of apoptotic cascades; (2) Par-4 alters APP processing during apoptosis through a calcium-dependent pathway; (3) Par-4 directly interacts with APP and alters intracellular Abeta production and/or extracellular pool of secreted APPs and Abeta under apoptotic and/or nonapoptotic conditions; (4) AATF is a novel interaction partner of Par-4 and functions as an endogenous negative regulator of Par-4 activity in APP processing. The proposed studies may establish Par-4 as a novel regulator of APP processing. Inhibition of Par-4 activity by enhancing AATF expression and/or manipulating Par-4/APP interaction may provide novel therapeutic implications for Alzheimer's disease.