Regulation of APP Processing by Par-4

描述(申请人提供)：我们最近发现亮氨酸拉链蛋白PAR-4(前列腺凋亡反应-4)是一种新的细胞死亡促进蛋白，与阿尔茨海默病(AD)的发病机制有关。重要的是，我们已经发现，PAR-4可能通过caspase依赖的途径参与对转基因IMR-32细胞中Abeta产生的调节(Guo Q等人，自然医学1998；4(8)：957-962，Guo Q等人，J.Biol。化学，2001年；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处理的一种新的调节因子。最近，我们发现PAR-4直接与APP相互作用，并改变Abeta的分泌。这些数据有力地表明，PAR-4至少通过两种不同的机制来调节APP的处理：(A)通过在凋亡过程中激活的caspase和钙依赖的途径，以及(B)通过与APP的直接物理相互作用。AATF是一种新的亮氨酸拉链蛋白，在神经元中表达。我们发现AATF直接与PAR-4结合并具有神经保护作用，提示AATF可能是PAR-4活性的内源性调节因子。拟开展的研究将采用一系列体外和体内方法验证以下假设：(1)PAR-4在APP启动凋亡级联反应后的异常APP加工中发挥重要作用；(2)PAR-4通过钙依赖途径改变APP的加工过程；(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Abeta的产生和/或细胞外分泌的APP和Abeta池；(4)AATF是PAR-4的新相互作用伙伴，在APP加工过程中作为PAR-4活性的内源性负调节因子发挥作用。拟议的研究可能会确立PAR-4作为APP处理的一种新的调节因子。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.