Elucidating a Role for A Transcription Factor in Neuronal Proteostasis

项目摘要 散发性神经退行性疾病在老年人群中普遍存在，但其起源仍然难以确定。 解释和治疗方案往往效果有限。虽然存在着巨大的多样性， 在这些疾病之间受影响的CNS的特定细胞类型或区域，它们通过共同的 特征：在垂死细胞内或周围形成蛋白质聚集体。从以下方面收集的见解： 研究可预测地赋予神经元中蛋白质聚集体形成的功能突变的丧失， 随后神经元死亡，使我们能够揭示神经元存活所必需的蛋白质稳定途径， 在人类神经退行性疾病的散发性和家族性形式中均被破坏。 我们的实验室使用正向遗传方法来识别对神经元功能至关重要的稳态途径， 生存最近我们在老鼠身上发现了一种自发突变， 从1月龄开始出现小脑浦肯野细胞聚集，随后出现进行性丢失和共济失调， 这种突变的纯合子小鼠。通过定位克隆，我们在Rreb 1锌基因中发现了一个突变， 与聚集体形成、神经元丢失和共济失调共分离的指状转录因子。有趣的是， 这种突变的杂合性也与浦肯野细胞丢失有关，尽管神经元死亡的发生与细胞凋亡有关。 这表明Rreb 1功能的丧失和神经元存活在神经元死亡时紧密相关。 剂量水平。 很少有转录因子与神经元蛋白质稳态的丧失相关，大多数研究集中在 由编码这些蛋白质的基因中的显性突变引起的错误折叠蛋白质的产生和/或清除 proteins.尽管对Rreb 1在神经系统中的作用知之甚少，但一些研究集中在 这种蛋白质在发育中调节转录的作用，引用了它通过 几个锌指结构域和募集组蛋白脱乙酰酶、组蛋白脱甲基酶和共阻遏物 复合物重塑染色质并最终控制基因表达。使用这种新颖的 神经变性，我将研究Rreb 1在神经元中的作用，并确定这种破坏是如何发生的。 基因导致蛋白质稳态失衡，最终导致神经元细胞死亡。

Project Summary Sporadic neurodegenerative disorders are prevalent in the aging population, yet their origins remain difficult to explain and treatment regimens often of limited effectiveness. Though tremendous diversity exists in the specific cell types or regions of the CNS affected between these diseases, they are linked by a common characteristic: the formation of protein aggregates in or surrounding dying cells. Insights gleaned from the study of loss of function mutations that predictably confer the formation of protein aggregates in neurons and subsequent neuron death, allow us to uncover proteostatic pathways essential for neuron survival that may be disrupted in both sporadic and familial forms of human neurodegenerative disorders. Our lab uses a forward genetic approach to identify homeostatic pathways critical to neuron function and survival. Recently we discovered a spontaneous mutation in mice that leads to the formation of protein aggregates followed by progressive loss of cerebellar Purkinje cells and ataxia beginning at 1 month of age in mice that are homozygous for this mutation. By positional cloning, we identified a mutation in the Rreb1 zinc finger transcription factor that co-segregates with aggregate formation, neuron loss, and ataxia. Interestingly, heterozygosity for this mutation is also associated with Purkinje cell loss, although the onset of neuron death is later and less severe, suggesting that loss of Rreb1 function and neuron survival are tightly linked at the dosage level. Few transcription factors have been associated with loss of neuronal proteostasis with most studies focused on the production and/or clearance of misfolded proteins caused by dominant mutations in genes encoding these proteins. Though little is known about the role of Rreb1 in the nervous system, several studies have focused on the role of this protein in regulating transcription in development, citing its ability to bind directly to DNA via several zinc finger domains and recruit histone deacetylases, histone demethylases, and co-repressor complexes to remodel chromatin and ultimately control gene expression. Using this novel model of neurodegeneration, I will investigate the role of Rreb1 in neurons and determine how the disruption of this gene leads to an imbalance in proteostasis and ultimately neuron cell death.