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: 10190823
• 负责人: Emily Griffin
• 金额: $ 3.86万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190823
• 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 零星的神经退行性疾病在老龄化的人群中很普遍，但它们的起源仍然很难 解释和治疗方案通常具有有限的有效性。虽然存在着巨大的多样性 这些疾病之间影响的中枢神经系统的特定细胞类型或区域，它们与常见 特征：在垂死细胞中或周围的蛋白质聚集体的形成。洞察力从 研究功能突变的丧失，可以预见地赋予神经元中蛋白质聚集体的形成 随后的神经元死亡，允许我们发现可能是神经元生存至关重要的蛋白抑制途径 人类神经退行性疾病的零星和家族形式受到破坏。 我们的实验室使用一种正向遗传方法来识别对神经元功能至关重要的稳态途径和 生存。最近，我们在小鼠中发现了一个自发突变，导致蛋白质的形成 骨料随后是小脑浦肯野细胞的逐渐丧失，共济失调从1个月开始 对于这种突变纯合的小鼠。通过位置克隆，我们确定了RREB1锌中的突变 手指转录因子与骨料形成，神经元丧失和共济失调共隔离。有趣的是， 尽管神经元死亡的开始是 以后且不那么严重，表明RREB1功能和神经元存活的丧失在 剂量水平。 很少有转录因子与神经元蛋白抑制的丧失有关，大多数研究都集中在 由编码这些基因的显性突变引起的错误折叠蛋白的产生和/或清除 蛋白质。尽管RREB1在神经系统中的作用知之甚少，但几项研究的重点是 该蛋白在调节发育中转录中的作用，理由是它通过直接结合DNA通过 几个锌指域和募集组蛋白脱乙酰基酶，组蛋白脱甲基酶和共抑制剂 复合物重塑染色质并最终控制基因表达。使用这个新颖的模型 神经变性，我将研究RREB1在神经元中的作用，并确定如何破坏此事 基因导致蛋白抑制性和最终神经元细胞死亡的失衡。