Defining a novel trigger for apoptosis

描述(申请人提供)：细胞凋亡是一种调节细胞生理的程序性细胞死亡。细胞应激可激活细胞凋亡，例如未折叠的蛋白质。我们利用小分子筛选的方法，发现了一种新的蛋白质，它可以调节线粒体外膜通透性，以响应未折叠蛋白质的表达。我们筛选了47,000个小分子，寻找那些可以防止多聚谷氨酰胺诱导PC12细胞凋亡的小分子，并确定了三种有效的化合物。使用亲和纯化方法，我们发现所有四个化合物都通过抑制同一靶点发挥作用。我们发现，在PC12细胞中表达多聚谷氨酰胺后，这种靶蛋白积聚在线粒体中，并通过诱导线粒体外膜通透性(MOMP)激活内在的凋亡途径。我们建议确定这些化合物抑制该蛋白促凋亡活性的机制，并确定该蛋白如何诱导MOMP，包括确定该蛋白在线粒体外膜上的结合伙伴。这些研究可能定义一条新的凋亡途径。公共卫生相关性：我们的目标是定义一种诱导神经元凋亡的新机制。这一机制可能与神经退行性变有关。这一机制的小分子抑制剂最终可能为神经退行性疾病提供新的治疗药物。

DESCRIPTION (provided by applicant): Apoptosis is a type of programmed cell death that regulates cellular physiology. Apoptosis can be activated by cell stresses, such as unfolded proteins. We have discovered a novel protein mediating mitochondrial outer membrane permeabilization in response to unfolded protein expression, using a small molecule screening approach. We screened 47,000 small molecules for those that could prevent polyglutamine- induced apoptosis in PC12 cells and identified three effective compounds. Using an affinity purification approach, we found that all four compounds act by inhibiting the same target. We found that upon expression of polyglutamine in PC12 cells, this target protein accumulates in mitochondria and activates the intrinsic apoptotic pathway by inducing mitochondrial outer membrane permeabilization (MOMP). We propose to define the mechanism by which these compounds inhibit the pro-apoptotic activity of this protein, and to determine how this protein induces MOMP, including identifying binding partners for this protein in the mitochondrial outer membrane. These studies may define a new apoptotic pathway. PUBLIC HEALTH RELEVANCE: Our goal is to define a new mechanism for inducing apoptosis in neurons. This mechanism may be involved in neurodegeneration. Small molecule inhibitors of this mechanism may eventually provide new therapeutic agents for neurodegenerative diseases.