Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD

确定 Stathmin-2 的功能和作为 ALS/FTD 治疗靶点的潜力

基本信息

  • 批准号:
    10370327
  • 负责人:
  • 金额:
    $ 79.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Cytoplasmic protein accumulations of the RNA/DNA binding protein TDP-43 are found in affected neurons in almost all instances of amyotrophic lateral sclerosis (ALS) and approximately 50% of frontotemporal dementia (FTD). Nuclear clearance of TDP-43 has been widely observed in affected neurons in sporadic ALS/FTD, evidence strongly supporting the proposal that TDP-43 loss of function is a key aspect of disease mechanism underlying ALS/FTD pathogenesis. We have identified that the mRNA encoding stathmin-2 is 1) an essential factor for axonal regeneration of axotomized iPSC-derived motor neurons and 2) the mRNA most affected by reduction in TDP-43 function, with a striking loss from motor neurons in sporadic ALS and inherited disease from GGGGCC expansion in C9orf72. Stathmin-2 is an abundant, direct binding partner of α/β-tubulin dimers in neuronal perikarya, axons, growth cones, and synapses, including neuromuscular junctions (NMJs). Using genome editing, we will identify the mechanism of TDP-43-dependent premature polyadenylation/cryptic splicing that suppresses stathmin-2 synthesis when TDP-43 levels are lowered. We will use genome editing of induced pluripotent stem cells (iPSCs) derived human motor neurons grown in compartmented chambers (that separate neuronal cell bodies, axons and growth cones) to determine how stathmin-2 functions in a) motor neuron maintenance/repair, b) axonal microtubule stabilization and/or dynamics, c) neuromuscular junction formation and/or stabilization, and d) how palmitoylation of stathmin-2 affects its axonal function(s). Genome wide CRISPR/Cas9 screens using flow cytometry and optical methods will be undertaken to identify factors that control stathmin-2 synthesis or accumulation. Finally, we will determine the consequences in mice of reduction or loss of stathmin-2 on motor neuron function and muscle innervation/denervation and whether reduction in stathmin-2 synergizes with TDP-43 mutation to drive motor neuron disease. Outcomes of these efforts will provide key insights for understanding basic aspects of axonal and synaptic neurobiology and for evaluating whether maintaining or restoring stathmin-2 is an attractive therapeutic option in sporadic ALS/FTD and ALS from its most frequent genetic cause, repeat expansion in C9orf72.
在受影响的神经元中发现了RNA/DNA结合蛋白TDP-43的细胞质蛋白积累

项目成果

期刊论文数量(0)
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Don W Cleveland其他文献

Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease
胶质细胞作为非细胞自主性神经退行性疾病的内在成分
  • DOI:
    10.1038/nn1988
  • 发表时间:
    2007-10-26
  • 期刊:
  • 影响因子:
    20.000
  • 作者:
    Christian S Lobsiger;Don W Cleveland
  • 通讯作者:
    Don W Cleveland
VEGF: multitasking in ALS
血管内皮生长因子:在肌萎缩侧索硬化症中的多任务处理
  • DOI:
    10.1038/nn0105-5
  • 发表时间:
    2005-01-01
  • 期刊:
  • 影响因子:
    20.000
  • 作者:
    Christine Vande Velde;Don W Cleveland
  • 通讯作者:
    Don W Cleveland

Don W Cleveland的其他文献

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{{ truncateString('Don W Cleveland', 18)}}的其他基金

In vivo modelling and therapy development for stathmin-2 loss in TDP-43 proteinopathies
TDP-43 蛋白病中 stathmin-2 缺失的体内建模和治疗开发
  • 批准号:
    10317404
  • 财政年份:
    2021
  • 资助金额:
    $ 79.73万
  • 项目类别:
Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD
确定 Stathmin-2 的功能和作为 ALS/FTD 治疗靶点的潜力
  • 批准号:
    10835733
  • 财政年份:
    2020
  • 资助金额:
    $ 79.73万
  • 项目类别:
Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis
染色体分离、非整倍性和肿瘤发生的机制
  • 批准号:
    10674798
  • 财政年份:
    2017
  • 资助金额:
    $ 79.73万
  • 项目类别:
Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis
染色体分离、非整倍性和肿瘤发生的机制
  • 批准号:
    9883009
  • 财政年份:
    2017
  • 资助金额:
    $ 79.73万
  • 项目类别:
Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis
染色体分离、非整倍性和肿瘤发生的机制
  • 批准号:
    10406521
  • 财政年份:
    2017
  • 资助金额:
    $ 79.73万
  • 项目类别:
Junior Faculty and Postdoctoral Fellows Career Development Workshop
初级教师和博士后研究员职业发展研讨会
  • 批准号:
    8720394
  • 财政年份:
    2014
  • 资助金额:
    $ 79.73万
  • 项目类别:
MUTANT SOD1 ASSOCIATION WITH MITOCHONDRIA
突变体 SOD1 与线粒体的关联
  • 批准号:
    8365861
  • 财政年份:
    2011
  • 资助金额:
    $ 79.73万
  • 项目类别:
PHOSPHORYLATION OF MAD1 BY TTK
TTK 磷酸化 MAD1
  • 批准号:
    8171354
  • 财政年份:
    2010
  • 资助金额:
    $ 79.73万
  • 项目类别:
CHARACTERIZATION OF THE PLK4 KINASE
PLK4 激酶的表征
  • 批准号:
    8171423
  • 财政年份:
    2010
  • 资助金额:
    $ 79.73万
  • 项目类别:
POST-TRANSLATIONAL MODIFICATION AND INTERACTING PROTEINS OF CENP-E
CENP-E 的翻译后修饰和相互作用蛋白
  • 批准号:
    8171370
  • 财政年份:
    2010
  • 资助金额:
    $ 79.73万
  • 项目类别:

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