Elucidating a Role for A Transcription Factor in Neuronal Proteostasis

阐明转录因子在神经元蛋白质稳态中的作用

• 批准号: 10458474
• 负责人: Emily Griffin
• 金额: $ 3.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458474
• 关键词: Affect; Age-Months; Ataxia; Behavioral; Binding; Brain; Cell Death; Cells; ChIP-seq; Characteristics; Chromatin Structure; Critical Pathways; DNA; Development; Disease; Effectiveness; Gene Expression; Genes; Genetic Transcription; Glean; Health; Heterozygote; Histone Deacetylase; Histones; Homeostasis; Human; Introns; Lead; Light; Link; Maintenance; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; N-terminal; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Pathologic; Pathway interactions; Play; Population; Production; Protein Isoforms; Proteins; Proteome; Purkinje Cells; RNA Splicing; Repressor Proteins; Retrotransposon; Role; Specificity; Testing; Transcript; Transcriptional Regulation; Transgenic Organisms; Treatment Protocols; Variant; Zinc Fingers; aging population; cell type; chromatin remodeling; differential expression; dosage; experimental study; genetic approach; genetic corepressor; histone demethylase; insight; loss of function mutation; misfolded protein; mutant; neuron loss; novel; positional cloning; prevent; promoter; protein aggregation; protein misfolding; proteostasis; recruit; transcription factor

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.

项目摘要 散发性神经退行性疾病在老年人群中很普遍，但其起源仍难以确定。 解释和治疗方案往往效果有限。尽管存在着巨大的多样性， 在这些疾病之间受影响的特定细胞类型或中枢神经系统区域，它们由一个共同的 特征：死亡细胞内或细胞周围形成蛋白质聚集体。从以下方面收集的洞察力 神经元和神经细胞中可预测形成蛋白质聚集体的功能突变的研究 随后的神经元死亡，使我们能够发现对神经元生存至关重要的蛋白抑制通路，这可能是 在人类神经退行性疾病的散发性和家族性形式中都被破坏。 我们的实验室使用一种正向遗传学方法来识别对神经元功能和 生死存亡。最近，我们在小鼠身上发现了一种自发突变，导致蛋白质的形成 1个月龄小脑浦肯野细胞进行性丧失和共济失调 这种突变纯合子的小鼠。通过定位克隆，我们鉴定了RREB1锌的一个突变 指转录因子，与聚集体形成、神经元丢失和共济失调共同分离。有趣的是， 这种突变的杂合性也与浦肯野细胞丢失有关，尽管神经元死亡的开始是 后来和不那么严重，表明RREB1功能的丧失和神经元存活在 剂量水平。 很少有转录因子与神经元蛋白平衡的丧失有关，大多数研究集中在 由编码这些蛋白质的基因的显性突变引起的错误折叠蛋白质的产生和/或清除 蛋白质。尽管人们对RREB1在神经系统中的作用知之甚少，但有几项研究集中在 这种蛋白质在发育过程中调节转录的作用，引用了它通过 几个锌指结构域和新建组蛋白去乙酰基酶、组蛋白去甲基酶和共抑制物 重组染色质并最终控制基因表达的复合体。使用这一新的模型 我将研究RREB1在神经元中的作用，并确定这种干扰是如何 基因导致蛋白平衡失衡，最终导致神经细胞死亡。