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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：
Erika L Holzbaur
金额：
$ 45.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
https://reporter.nih.gov/project-details/9896888
关键词：
ALS patients Address Affect Afferent Neurons Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Autophagocytosis Autophagosome Axon Axonal Transport Back Biochemical Biogenesis Cell physiology Cellular Assay Cellular Stress Charcot-Marie-Tooth Disease Clinical Data Defect Degenerative Disorder Degradation Pathway Disease Dynein ATPase Goals Heritability Homeostasis Human Huntington Disease Image In Vitro Intervention Intracellular Transport Kinesin Lead Length Link Lysosomes MAPK8 gene Mediating Microtubules Modeling Molecular Motors Motor Motor Neurons Movement Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organelles Pathogenicity Pathologic Pathology Pathway interactions Phosphotransferases Proteins Regulation Regulatory Pathway Resolution Role Spinal Muscular Atrophy Testing Therapeutic Vesicle axonal degeneration dynactin experimental study gene therapy genetic analysis insight live cell imaging meter motor neuron degeneration mouse model neuron loss protein aggregation reconstitution response retrograde transport single molecule stressor vesicle 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：
Developmental cell
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：
CURRENT OPINION IN NEUROBIOLOGY
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：
Neuroscience letters
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：
Proceedings of the National Academy of Sciences of the United States of America
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：
The Journal of neuroscience : the official journal of the Society for Neuroscience
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