Functional analysis of Attractin-Mahogunin signaling

Attractin-Mahogunin 信号传导的功能分析

• 批准号: 7249350
• 负责人: Teresa M Gunn
• 金额: $ 35.85万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7249350
• 关键词: Adult; Aging; Alleles; Alternative Splicing; Alzheimer' s Disease; Animal Model; Antibodies; Biochemical; Biological Assay; Brain; CNS degeneration; Cells; Cessation of life; Color; Complex; Defect; Disease; Evaluation; Fingers; Gene Expression; Genes; Goals; Homologous Gene; Immunohistochemistry; In Vitro; Laboratories; Lead; Mammalian Cell; Mediating; Methods; Modeling; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathway interactions; Pattern; Phenotype; Physiological; Pigmentation physiologic function; Pigments; Protein Isoforms; Proteins; Research; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Transgenic Mice; Two-Hybrid System Techniques; Ubiquitin; Ubiquitination; Upper arm; Yeasts; attractin protein; base; gene function; in vivo; mahogunin protein; mutant; neuron loss; parkin gene/protein; protein aggregate; ubiquitin-protein ligase; yeast two hybrid system

DESCRIPTION (provided by applicant): Neurodegenerative disorders such as Alzheimer's and Parkinson's disease are common and devastating diseases, but the mechanism leading to neuronal death is not well understood. Mice with mutations in the Attractin (Atrn) and Mahogunin (Mgn) genes develop progressive spongy degeneration of the brain and thus represent newly recognized models of neurodegeneration. These mutants also have a coat color phenotype due to a defect in a pigment-cell specific pathway. The similarity between Atrn and Mgn mutants for two unrelated phenotypes suggests a common function for these genes. While the role of Atrn in neurons is unclear, Mgn encodes a RING-finger containing protein that acts as a ubiquitin ligase (E3) in vitro. Accumulation of ubiquitinated protein aggregates is a hallmark of many neurodegenerative disorders and mutations in another E3, Parkin, cause a familial form of Parkinson's disease. Thus, we hypothesize that defects in ubiquitin-mediated degradation of specific target proteins lead to neuronal death in Atrn and Mgn mutants. The long-term goal of research in the Gunn laboratory is to determine how. The short term goals are to test the following hypotheses: 1) that Mgn functions as an E3 in vivo, by testing whether the RING domain of Mgn (required for E3 activity in vitro) is essential for normal Mgn function in vivo, and by identifying Mgn-interacting proteins using a yeast two hybrid assay and using biochemical assays to test whether these proteins are targeted by Mgn for ubiquitin-mediated decay and accumulate in the brains of Mgn mutant mice. 2) that Mgn and Atrn act in the same pathway, using marker gene expression, western analysis and/or immunohistochemistry to examine Mgn levels and localization in Atrn mutants and determine whether proteins identified as Mgn targets for ubiquitination accumulate in the brains of Atrn mutant mice. 3) that a newly discovered Atrn homolog, Lurin, signals through the Mgn pathway, by generating mice lacking Lurin and examining their phenotype (including accumulation of Mgn targets) on normal and Atrn null backgrounds. As Mgn mutants display some phenotypes not observed in Atrn mutants, Lrn may compensate for loss of Atrn in some tissues and loss of both Lrn and Atrn may recapitulate the full Mgn phenotype.

描述(申请人提供)：神经退行性疾病，如阿尔茨海默氏症和帕金森氏病是常见的和破坏性的疾病，但导致神经元死亡的机制尚不清楚。带有Attractin(Atrn)和Mahogunin(MGN)基因突变的小鼠会出现进行性的脑部海绵状变性，因此代表了新发现的神经退化模型。由于色素细胞特定途径的缺陷，这些突变体也具有毛色表型。Atrn和MGN突变体在两个不相关的表型上的相似性表明这些基因具有共同的功能。虽然Atrn在神经元中的作用尚不清楚，但MGN编码一种含有环指的蛋白质，在体外起泛素连接酶(E3)的作用。泛素化蛋白聚集体的积累是许多神经退行性疾病的标志，另一种E3基因帕金森氏症的突变会导致家族性帕金森氏症。因此，我们假设，在Atrn和MGN突变体中，泛素介导的特定靶蛋白降解的缺陷导致神经元死亡。冈恩实验室研究的长期目标是确定如何进行。 短期目标是检验以下假设： 1)MGN在体内作为E3发挥作用，方法是测试MGN的环状结构域(体外E3活动所需)是否对MGN在体内的正常功能至关重要，并使用酵母双杂交试验鉴定MGN相互作用的蛋白，并使用生化分析来测试MGN是否针对泛素介导的衰退并在MGN突变小鼠的大脑中积累这些蛋白。 2)MGN和Atrn以相同的途径发挥作用，利用标记基因表达、Western分析和/或免疫组织化学方法检测MGN在Atrn突变中的水平和定位，并确定被确认为泛素化MGN靶点的蛋白质是否在Atrn突变小鼠的脑中积累。 3)新发现的Atrn同源基因Lurin通过MGN途径发出信号，通过产生小鼠 缺乏Lurin，并在正常和Atrn零背景下检查他们的表型(包括MGN靶标的积累)。由于MGN突变体表现出一些在Atrn突变体中没有观察到的表型，LRN可能补偿某些组织中Atrn的丢失，LRN和Atrn的丢失可能概括了完整的MGN表型。

项目成果

Transgenic analysis of the physiological functions of Mahogunin Ring Finger-1 isoforms.

• DOI: 10.1002/dvg.20529
• 发表时间: 2009-08
• 期刊: GENESIS
• 影响因子: 1.5
• 作者: Jiao, Jian;Kim, Hae Young;Liu, Roy R.;Hogan, Carolyn A.;Sun, Kaihua;Tam, Lori Mon;Gunn, Teresa M.
• 通讯作者: Gunn, Teresa M.

MGRN1-dependent pigment-type switching requires its ubiquitination activity but not its interaction with TSG101 or NEDD4.

MGRN1依赖性色素类型开关需要其泛素化活性，而不是与TSG101或NEDD4的相互作用。

• DOI: 10.1111/pcmr.12059
• 发表时间: 2013-03
• 期刊: Pigment cell & melanoma research
• 影响因子: 4.3
• 作者: Gunn TM;Silvius D;Bagher P;Sun K;Walker KK
• 通讯作者: Walker KK

Abnormal regulation of TSG101 in mice with spongiform neurodegeneration.

• DOI: 10.1016/j.bbadis.2009.08.009
• 发表时间: 2009-10
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
• 影响因子: 6.2
• 作者: Jiao, Jian;Sun, Kaihua;Walker, Will P.;Bagher, Pooneh;Cota, Christina D.;Gunn, Teresa M.
• 通讯作者: Gunn, Teresa M.