INVESTIGATING THE ROLE OF THE CYTOSKELETON IN NEURODEGENERATION

研究细胞骨架在神经变性中的作用

• 批准号: 10678644
• 负责人: Morgan Catherine Stephens
• 金额: $ 4.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678644
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Actins; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; American; Automobile Driving; Autophagocytosis; Behavior; Behavioral; Biochemical; Biological Assay; Biological Models; Brain; Cause of Death; Cell model; Cells; Clinical; Color; Communication; Complex; Cytoskeleton; Data; Dementia; Dendritic Spines; Deposition; Development; Disease; Disease Progression; Distal; Drosophila genus; Environment; Etiology; Genes; Genetic; Genetic Screening; Goals; Harvest; Histologic; Histology; Human; Human Cell Line; Huntington Disease; Impairment; In Vitro; LIM Domain; Lysosomes; Malignant Neoplasms; Measures; Mediating; Microfilaments; Microscopy; Modeling; Modification; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phase; Phosphotransferases; Prevalence; Process; Proteins; Regulation; Research; Resolution; Rod; Role; Senile Plaques; Societies; Synapses; System; Tauopathies; Techniques; Therapeutic; Therapeutic Intervention; Transmission Electron Microscopy; Ubiquitin; United States; Vesicle; Western Blotting; actin depolymerizing factor; attenuation; brain tissue; cofilin; combat; density; disability; extracellular; histological studies; hyperphosphorylated tau; improved; in vitro Assay; in vivo; induced pluripotent stem cell; insight; knock-down; misfolded protein; mouse model; multicatalytic endopeptidase complex; nerve stem cell; neurodegenerative phenotype; neuroinflammation; neuropathology; neurotoxic; new therapeutic target; novel; overexpression; prevent; protein aggregation; protein degradation; proteostasis; response; tau Proteins; tau aggregation; therapeutic development; therapeutic target; trafficking; vesicle transport; wasting

Project Summary/Abstract: Neurodegenerative diseases are among the fastest growing clinical burdens on society, and in the next 20 years Alzheimer’s Disease (AD) is projected to overtake cancer as the second leading cause of death in adults. Despite AD prevalence, there are currently no therapeutic interventions to combat the underlying pathology driving disease progression. While much is still not understood about neurodegenerative pathogenesis, the accumulation of extracellular amyloid- plaques and intracellular tau tangles are undisputed hallmarks of AD. To combat disease progression, an attractive therapeutic strategy is to investigate impairments in native proteostatic mechanisms used to dispose of this neurotoxic protein accumulation. One such mechanism which has been implicated in the development and progression of not only AD, but numerous neurodegenerative proteinopathy disorders including Parkinson’s and Huntington’s disease, is the autophagy-lysosomal network (ALN). The ALN is a bulk degradative system utilizing vesicular transport to dispose of large protein aggregates which contribute to neuronal dysfunction. This process relies on the active remodeling of the actin cytoskeleton to initiate, capture, and transport neurotoxic cargo for degradation and maintain proper proteostasis. However, mechanistically how dysregulations in cytoskeletal dynamics are associated with neurodegenerative pathology contributing to disease remains unclear. Through multiple behavioral neurodegenerative screens, we have identified an actin depolymerizing factor, cofilin, along with its upstream molecular regulators, which upon modulation improve neurodegenerative behavioral deficits and lower tau accumulation in vivo. This proposal seeks to investigate how cytoskeletal dynamics contribute to AD through genetic attenuation of the cofilin-centric cytoskeletal remodeling pathway. I hypothesize that modulating the activity of cofilin and its regulators will ameliorate AD neurodegenerative phenotypes via modification of the cytoskeleton and proteostasis. Aim 1 will utilize behavioral and histological approaches to investigate how genetic modulation of numerous genes within the remodeling pathway influence neurodegenerative phenotypes in tauopathy Drosophila and mouse models. In Aim 2, I will investigate mechanistically how this cytoskeletal remodeling pathway is involved in the formation and progression of the ALN through 1) measuring changes in neurotoxic protein accumulation upon cytoskeletal genetic modulation using various tauopathy model systems, and 2) utilizing high resolution microscopy techniques in AD patient derived induced pluripotent stem cells (iPSCs) along with biochemical in vitro assays, to investigate how genetically modulating cofilin disrupts various phases of the ALN. Upon successful completion of this project, we will identify molecular impairments of cytoskeletal remodeling associated with neurodegeneration that are involved in proteostatic imbalances and disease pathogenesis. Furthermore, we hope to identify novel therapeutic targets within this pathway capable of treating not only AD, but multiple neurodegenerative diseases caused by neurotoxic protein accumulation.

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