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（由申请人提供）：诸如阿尔茨海默氏病和帕金森氏病等神经退行性疾病是常见的疾病，但导致神经元死亡的机制尚不清楚。具有诱导蛋白（ATRN）和Mahogunin（MGN）基因突变的小鼠会发展出大脑的渐进性海绵状变性，因此代表了新认识的神经变性模型。这些突变体由于在色素细胞特异性途径中的缺陷而具有外套颜色表型。两种无关表型的ATRN和MGN突变体之间的相似性表明了这些基因的共同功能。虽然ATRN在神经元中的作用尚不清楚，但MGN在体外编码了一个含有蛋白质的无名指，该蛋白在体外充当泛素连接酶（E3）。泛素化蛋白聚集体的积累是另一个E3中许多神经退行性疾病和突变的标志，引起了帕金森氏病的家族形式。因此，我们假设泛素介导的特定靶蛋白降解的缺陷导致ATRN和MGN突变体的神经元死亡。在Gunn实验室进行研究的长期目标是确定如何。 短期目标是检验以下假设： 1）通过测试MGN的环域（E3活性在体外所必需的）对于在体内的正常功能以及使用MGN相互作用的蛋白质使用酵母两个混合分析和使用生物化学依赖于Mgn的Mgn raindied Mentied Mentied undied Metiquiquiquiquiquiquiquiquiquiquiquiquiquiquiquiquiquiquiquique 1）老鼠。 2）MGN和ATRN在同一途径中起作用，使用标记基因表达，西方分析和/或免疫组织化学来检查ATRN突变体中的MGN水平和定位，并确定是否鉴定为蛋白质的蛋白质是否鉴定为泛素化的MGN靶标的泛素化，积累在ATRN突变体小鼠的大脑中。 3）通过产生小鼠，新发现的通过MGN途径的ATRN同源物（通过MGN途径）信号 缺乏Lurin并检查其表型（包括MGN靶标的积累）在正常和ATRN无效背景上。由于MGN突变体在ATRN突变体中未观察到一些表型，因此LRN可能会补偿某些组织中ATRN的损失，并且LRN和ATRN的损失可能会概括完整的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.

• 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.