Defining a novel trigger for apoptosis

描述（由申请人提供）：细胞凋亡是一种调节细胞生理学的程序性细胞死亡。细胞凋亡可以被细胞应激激活，例如未折叠蛋白。我们已经发现了一种新的蛋白质介导的线粒体外膜透化响应未折叠的蛋白质表达，使用小分子筛选方法。我们筛选了47，000种小分子，以防止PC12细胞中聚谷氨酰胺诱导的凋亡，并鉴定了三种有效化合物。使用亲和纯化方法，我们发现所有四种化合物都通过抑制相同的靶标起作用。我们发现，在PC12细胞中的多聚谷氨酰胺的表达后，这种靶蛋白在线粒体中积累，并通过诱导线粒体外膜透化（MOMP）激活内在的凋亡途径。我们建议定义这些化合物抑制这种蛋白质的促凋亡活性的机制，并确定这种蛋白质如何诱导MOMP，包括确定这种蛋白质在线粒体外膜中的结合伙伴。这些研究可能会定义一个新的凋亡途径。公共卫生相关性：我们的目标是确定一种诱导神经元凋亡的新机制。这种机制可能与神经退行性变有关。这种机制的小分子抑制剂可能最终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.