Mechanistic analysis of axonal transport defects in neurodegenerative disease
神经退行性疾病轴突运输缺陷的机制分析
基本信息
- 批准号:9896888
- 负责人:
- 金额:$ 45.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2021-03-31
- 项目状态:已结题
- 来源:
- 关键词:ALS patientsAddressAffectAfferent NeuronsAgingAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisAutophagocytosisAutophagosomeAxonAxonal TransportBackBiochemicalBiogenesisCell physiologyCellular AssayCellular StressCharcot-Marie-Tooth DiseaseClinicalDataDefectDegenerative DisorderDegradation PathwayDiseaseDynein ATPaseGoalsHeritabilityHomeostasisHumanHuntington DiseaseImageIn VitroInterventionIntracellular TransportKinesinLeadLengthLinkLysosomesMAPK8 geneMediatingMicrotubulesModelingMolecular MotorsMotorMotor NeuronsMovementMutationNerve DegenerationNeurodegenerative DisordersNeuronsOrganellesPathogenicityPathologicPathologyPathway interactionsPhosphotransferasesProteinsRegulationRegulatory PathwayResolutionRoleSpinal Muscular AtrophyTestingTherapeuticVesicleaxonal degenerationdynactinexperimental studygene therapygenetic analysisinsightlive cell imagingmetermotor neuron degenerationmouse modelneuron lossprotein aggregationreconstitutionresponseretrograde transportsingle moleculestressorvesicle transport
项目摘要
Project Summary
Mutations in cytoplasmic dynein or its activator dynactin are causative for neuronal diseases including heritable
forms of motor neuron degeneration and CharcotMarieTooth disease. More broadly, we know that defects in
dyneindriven functions such as retrograde axonal transport are involved in the pathogenic mechanisms of
neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington’s, and Alzheimer’s.
However, the specific mechanisms involved remain unclear. Dynein is a pleiotropic cellular motor with multiple
distinct roles in the neuron. Here we will focus on the hypothesis that defects in the dyneindriven retrograde
transport of degradative organelles including lysosomes and autophagosomes are major contributors to the
axonal degeneration that characterize these diseases. The goal of this proposal is to understand the specific
mechanisms linking defects in dynein function to neurodegeneration, focusing on the following three aims: (1)
How is retrograde axonal transport altered during neurodegeneration? We hypothesize that pathological
alterations in the JNK and Cdk5 pathways lead to the dysregulation of opposing microtubule motors during
axonal transport. We will test this hypothesis using quantitative live cell imaging of vesicular transport in
primary neurons from multiple models of ALS. Then, we will mechanistically dissect how kinase misregulation
affects motor function using in vitro reconstitution approaches with single molecule resolution. These studies
will test the model that a disruption in the coordination of oppositelyoriented motors is the primary defect
leading to altered transport along the axon. (2) What are the pathways for autophagosome biogenesis and
cargoloading in the neuron? We hypothesize that autophagy in the neuron follows a stereotypical and
spatially regulated pathway that is required to maintain cellular homeostasis. We will examine autophagosome
biogenesis and cargoloading in primary sensory and motor neurons using quantitative live cell imaging,
focusing on the roles of dynein and optineurin. Then we will determine how this pathway responds to cellular
stressors, to address the hypothesis that this pathway has a limited ability to upregulate in response to cellular
stress. (3) How do defects in dyneindriven autophagy lead to degeneration of the axon? We
hypothesize that the active, dyneindriven transport of autophagosomes is tightly linked to function, and that
defects in transport will lead to defective degradation of aging organelles and aggregated proteins. We will use
live imaging and biochemical and cellular assays to determine how defects in autophagosome transport along
the axon contribute to neurodegeneration and how distinct dynein mutations differentially perturb cellular
functions, leading to disparate clinical manifestations. Mutations in cytoplasmic dynein are sufficient to cause
human neurodegenerative diseases including spinal muscular atrophy (SMALED) and CharcotMarieTooth
disease (Type 2O), but the mechanisms involved remain to be determined. Progress on these aims should
offer new opportunities for therapeutic approaches or clinical intervention.
项目摘要
细胞质动力蛋白或其激活因子动力蛋白的突变可导致神经性疾病,包括遗传性疾病
运动神经元变性和Charcot Marie Tooth病的形式。更广泛地说,我们知道
动力蛋白驱动的功能,如逆行轴突运输,参与了糖尿病的发病机制。
神经退行性疾病,包括肌萎缩侧索硬化症(ALS)、亨廷顿氏症和阿尔茨海默氏症。
然而,具体涉及的机制仍不清楚。动力蛋白是一种多效性细胞马达,具有多个
在神经元中扮演不同的角色。在这里,我们将重点研究动力蛋白驱动的逆行中的缺陷这一假设
包括溶酶体和自噬在内的降解细胞器的运输是导致
以这些疾病为特征的轴突变性。这项建议的目标是了解具体的
将动力蛋白功能缺陷与神经退行性变联系起来的机制主要集中在以下三个目标:(1)
在神经退行性变过程中,逆行轴突运输是如何改变的?我们假设病态的
JNK和CDK5通路的改变导致对立的微管马达在
轴突运输。我们将使用囊泡运输的定量活细胞成像来验证这一假设
来自多种ALS模型的原代神经元。然后,我们将机械地剖析激酶是如何错误调节的
使用单分子分辨率的体外重建方法影响运动功能。这些研究
将测试模型,即方向相反的电机协调中断是主要缺陷
导致沿着轴突的运输发生改变。(2)自噬小体生物发生的途径有哪些
在神经元中装载货物?我们假设神经元中的自噬遵循刻板印象
维持细胞内稳态所需的空间调节途径。我们将检查自噬小体
利用定量活细胞成像技术在初级感觉神经元和运动神经元中的生物发生和载物
重点研究动力蛋白和视神经磷酸酶的作用。然后我们将确定这一途径如何响应细胞
应激源,以解决这一途径对细胞反应的上调能力有限的假设
压力。(3)动力蛋白驱动的自噬缺陷是如何导致轴突退化的?我们
假设主动的、动力蛋白驱动的自噬小体的运输与功能密切相关,并且
运输过程中的缺陷会导致老化细胞器和聚集蛋白的缺陷降解。我们将使用
用活体成像、生化和细胞分析来确定自噬小体中的缺陷如何运输
轴突导致神经变性以及不同的动力蛋白突变是如何不同地扰乱细胞的
功能,导致不同的临床表现。细胞质动力蛋白的突变足以导致
人类神经退行性疾病包括脊髓性肌萎缩症(SMA-LED)和Charcot-Marie-Tooth
疾病(2O型),但涉及的机制仍有待确定。在实现这些目标方面应取得进展
为治疗方法或临床干预提供新的机会。
项目成果
期刊论文数量(27)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
What Doesn't Kill You Makes You Stronger.
那些杀不死你的会让你变得更强大。
- DOI:10.1016/j.devcel.2018.11.003
- 发表时间:2018
- 期刊:
- 影响因子:11.8
- 作者:Stavoe,AndreaKH;Holzbaur,ErikaLF
- 通讯作者:Holzbaur,ErikaLF
Vesicular degradation pathways in neurons: at the crossroads of autophagy and endo-lysosomal degradation
- DOI:10.1016/j.conb.2019.01.005
- 发表时间:2019-08-01
- 期刊:
- 影响因子:5.7
- 作者:Boecker, C. Alexander;Holzbaur, Erika L. F.
- 通讯作者:Holzbaur, Erika L. F.
Axonal autophagy: Mini-review for autophagy in the CNS.
- DOI:10.1016/j.neulet.2018.03.025
- 发表时间:2019-04-01
- 期刊:
- 影响因子:2.5
- 作者:Stavoe AKH;Holzbaur ELF
- 通讯作者:Holzbaur ELF
ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy.
- DOI:10.1073/pnas.2025053118
- 发表时间:2021-06-15
- 期刊:
- 影响因子:11.1
- 作者:Harding O;Evans CS;Ye J;Cheung J;Maniatis T;Holzbaur ELF
- 通讯作者:Holzbaur ELF
Neuroligin 1 is dynamically exchanged at postsynaptic sites.
- DOI:10.1523/jneurosci.0896-10.2010
- 发表时间:2010-09-22
- 期刊:
- 影响因子:0
- 作者:Schapitz IU;Behrend B;Pechmann Y;Lappe-Siefke C;Kneussel SJ;Wallace KE;Stempel AV;Buck F;Grant SG;Schweizer M;Schmitz D;Schwarz JR;Holzbaur EL;Kneussel M
- 通讯作者:Kneussel M
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Erika L Holzbaur其他文献
Erika L Holzbaur的其他文献
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{{ truncateString('Erika L Holzbaur', 18)}}的其他基金
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
- 批准号:
9922337 - 财政年份:2018
- 资助金额:
$ 45.83万 - 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
- 批准号:
10621591 - 财政年份:2018
- 资助金额:
$ 45.83万 - 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
- 批准号:
10155504 - 财政年份:2018
- 资助金额:
$ 45.83万 - 项目类别:
Mechanistic analysis of axonal transport defects in neurodegenerative disease
神经退行性疾病轴突运输缺陷的机制分析
- 批准号:
9617503 - 财政年份:2018
- 资助金额:
$ 45.83万 - 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
- 批准号:
10397408 - 财政年份:2018
- 资助金额:
$ 45.83万 - 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
- 批准号:
8270484 - 财政年份:2008
- 资助金额:
$ 45.83万 - 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
- 批准号:
7524459 - 财政年份:2008
- 资助金额:
$ 45.83万 - 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
- 批准号:
8079649 - 财政年份:2008
- 资助金额:
$ 45.83万 - 项目类别:
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