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.
项目总结
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:
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:
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:
8079649 - 财政年份:2008
- 资助金额:
$ 45.83万 - 项目类别:
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