Attractin, Mahogunin, and Neurodegeneration

Attractin、Mahogunin 和神经退行性疾病

基本信息

  • 批准号:
    7386344
  • 负责人:
  • 金额:
    $ 7.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-15 至 2009-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The long term goal of this study is to determine the functions of two novel genes, attractin (Atrn) and mahogunin (Mgrn1), in age-related neurodegeneration. Atrn and Mgrn1, which were originally identified to be in the same genetic pathways to regulate pigmentation, have been shown to cause age-related neurodegeneration. Loss-of-function mutations of Atrn or Mgrn1 result in similar widespread neurological abnormalities including neuronal cell death, hypomyelination and vacuolation, accompanied by body tremor. A progressive loss of substantia nigra neurons has been observed in spontaneous mutant rats with Atrn deficiency. Atrn encodes a transmembrane protein, while Mgrn1 encodes an intracellular E3 ubiquitin ligase, which is an important component in the ubiquitin-proteasome system (UPS). Phenotypic rescue studies in mice suggest that Mgrn1 might lie genetically downstream of Atrn in the regulation of pigmentation. However, whether this is also true for the neurodegeneration phenotype, how Atrn and Mgrn1 cross-talk, and whether they represent two components in the same intracellular signaling pathway are unknown. The abnormality of the UPS is one of the common features shared by several known neurodegeneration disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). It raises a question of whether Atrn and Mgrn1 are involved in the pathogenesis of these known age-related neurodegenerative diseases. Our preliminary data provided evidence that these two genes play a role in the survival of dopaminergic neuronal cells. We found that reducing the endogenous expression level of Atrn or Mgrn1 exacerbates, whereas overexpressing Atrn or Mgrn1 protects against, the dopaminergic neuronal cell death caused by neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) or lactacystin (a proteasome inhibitor) in vitro (preliminary data). Both neurotoxins induce Parkinson-like syndromes in animal models. Furthermore, for the first time, we demonstrated that vast majority of the dopamine neurons (>95%) in the substantia nigra of mice express both Atrn and Mgrn1 (preliminary data), providing the anatomical and molecular basis for potential direct influences of Atrn and Mgrn1 on the nigrostriatal dopamine system. We hypothesize that transgenic expression of Atrn protects dopamine neurons in the substantia nigra and that Mgrn1 functions as a downstream molecule mediating Atrn's actions on the survival of dopaminergic neurons. To test this hypothesis, we have two specific aims: Specific Aim 1. Determine whether transgenic expression of Atrn in mice protects the dopamine neurons in the SN using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Specific Aim 2. Determine whether Atrn regulates dopaminergic neuronal survival via Mgrn1. Identifying the genes that are involved in the pathogenesis and mechanisms of neurodegenerative diseases will help us to develop new treatment strategies for these diseases. Based upon our preliminary data, we propose to determine the protective role of Atrn and Mgrn1 both in vitro and in vivo using a PD disease model. The studies will lead to possible new mechanisms of the pathogenesis and therapeutic interventions for both PD and other neurodegenerative diseases.
描述(由申请人提供):本研究的长期目标是确定两个新基因,吸引力(Atrn)和桃花素(Mgrn1)在年龄相关神经变性中的功能。Atrn和Mgrn1,最初被确定在相同的遗传途径中调节色素沉着,已被证明会导致与年龄相关的神经变性。Atrn或Mgrn1的功能丧失突变导致类似的广泛的神经系统异常,包括神经元细胞死亡、髓鞘退化和空泡形成,并伴有身体震颤。在Atrn缺乏的自发突变大鼠中观察到黑质神经元的进行性丢失。Atrn编码一种跨膜蛋白,而Mgrn1编码细胞内E3泛素连接酶,这是泛素-蛋白酶体系统(UPS)的重要组成部分。小鼠的表型拯救研究表明,Mgrn1可能位于Atrn的遗传下游,参与色素沉着的调节。然而,对于神经变性表型是否也是如此,Atrn和Mgrn1如何相互作用,以及它们是否代表同一细胞内信号通路中的两个组成部分,这些都是未知的。UPS异常是几种已知神经退行性疾病(如帕金森病(PD)、阿尔茨海默病(AD)和肌萎缩侧索硬化症(ALS))的共同特征之一。这就提出了一个问题,即Atrn和Mgrn1是否参与了这些已知的与年龄相关的神经退行性疾病的发病机制。我们的初步数据提供了这两个基因在多巴胺能神经元细胞的存活中发挥作用的证据。我们发现,降低内源性Atrn或Mgrn1的表达水平会加剧多巴胺能神经元细胞的死亡,而过表达Atrn或Mgrn1则可以防止神经毒素、1-甲基-4-苯基吡啶(MPP+)或乳酸蛋白酶(一种蛋白酶体抑制剂)在体外引起的多巴胺能神经元细胞死亡(初步数据)。在动物模型中,这两种神经毒素都会诱发帕金森样综合征。此外,我们首次证明了小鼠黑质中绝大多数多巴胺神经元(>95%)同时表达Atrn和Mgrn1(初步数据),为Atrn和Mgrn1对黑质纹状体多巴胺系统的潜在直接影响提供了解剖学和分子基础。我们假设Atrn的转基因表达保护了黑质中的多巴胺神经元,而Mgrn1作为下游分子介导Atrn对多巴胺能神经元存活的作用。为了验证这一假设,我们有两个具体目标:利用PD的1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)模型,确定转基因Atrn在小鼠体内的表达是否保护SN中的多巴胺神经元。具体目标2。确定Atrn是否通过Mgrn1调控多巴胺能神经元存活。

项目成果

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Wei Zhang其他文献

Structural, elastic, magnetic and electronic properties of 4d perovskite CaTcO3: a DFT+U investigation
4d 钙钛矿 CaTcO3 的结构、弹性、磁性和电子特性:DFT U 研究
  • DOI:
    10.1088/0953-8984/24/18/185401
  • 发表时间:
    2012-05
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Wei Zhang;Peiqing Tong
  • 通讯作者:
    Peiqing Tong
Synthesis of Obyanamide, a Marine Cytotoxic Cyclic Depsipeptide
海洋细胞毒性环缩酚肽 Obyanamide 的合成
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    9.1
  • 作者:
    Ni Song;Wei Zhang;Yingxia Li;Zhongzhen Li
  • 通讯作者:
    Zhongzhen Li
Fault tolerant control for uncertain fuzzy systems with actuator failure
执行器故障的不确定模糊系统的容错控制
A panel of miRNAs as prognostic indicators for clinical outcome of skin cutaneous melanoma
一组 miRNA 作为皮肤黑色素瘤临床结果的预后指标

Wei Zhang的其他文献

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{{ truncateString('Wei Zhang', 18)}}的其他基金

Light triggered materials for on-demand local anesthesia and tissue adhesive dissolution
用于按需局部麻醉和组织粘合剂溶解的光触发材料
  • 批准号:
    10368292
  • 财政年份:
    2022
  • 资助金额:
    $ 7.3万
  • 项目类别:
Structural Mechanisms of Alphavirus Membrane Fusion
甲病毒膜融合的结构机制
  • 批准号:
    10444088
  • 财政年份:
    2022
  • 资助金额:
    $ 7.3万
  • 项目类别:
Structural Mechanisms of Alphavirus Membrane Fusion
甲病毒膜融合的结构机制
  • 批准号:
    10612929
  • 财政年份:
    2022
  • 资助金额:
    $ 7.3万
  • 项目类别:
Light triggered materials for on-demand local anesthesia and tissue adhesive dissolution
用于按需局部麻醉和组织粘合剂溶解的光触发材料
  • 批准号:
    10613962
  • 财政年份:
    2022
  • 资助金额:
    $ 7.3万
  • 项目类别:
A New Versatile, SERS-based GPCR assay
一种新型多功能、基于 SERS 的 GPCR 检测
  • 批准号:
    10324451
  • 财政年份:
    2021
  • 资助金额:
    $ 7.3万
  • 项目类别:
High Capacity UltraFISH for Single-cell Spatial Transcriptomics
用于单细胞空间转录组学的高容量 UltraFISH
  • 批准号:
    9909612
  • 财政年份:
    2020
  • 资助金额:
    $ 7.3万
  • 项目类别:
Temporal Single Cell RNAseq to Identify Genes and Pathways Affected by 15q11.2 Duplication in Autism iPSC-Derived Differentiating Cortical Neurons
时间单细胞 RNAseq 识别自闭症 iPSC 衍生的分化皮质神经元中受 15q11.2 重复影响的基因和通路
  • 批准号:
    9200627
  • 财政年份:
    2016
  • 资助金额:
    $ 7.3万
  • 项目类别:
Patient iPSC derived neural synaptic screen for drug discovery
用于药物发现的患者 iPSC 衍生神经突触筛选
  • 批准号:
    9141432
  • 财政年份:
    2016
  • 资助金额:
    $ 7.3万
  • 项目类别:
The essential role of gamma-secretase in human papillomavirus infection
γ-分泌酶在人乳头瘤病毒感染中的重要作用
  • 批准号:
    8783864
  • 财政年份:
    2014
  • 资助金额:
    $ 7.3万
  • 项目类别:
Characterization of oncogenic FGFR3-TACC3 fusion gene in glioblastoma
胶质母细胞瘤中致癌 FGFR3-TACC3 融合基因的特征
  • 批准号:
    8967572
  • 财政年份:
    2013
  • 资助金额:
    $ 7.3万
  • 项目类别:
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