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VPS35 D620N inhibits autophagy through disrupted hyaluronic acid-CD44 signaling

VPS35 D620N 通过破坏透明质酸-CD44 信号传导抑制自噬

基本信息

批准号：
10415177
负责人：
Brad Morrison
金额：
$ 20.71万
依托单位：
BOISE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415177
关键词：
Address Affect Applications Grants Area Attention Autophagocytosis Biology Brain CD44 gene Cancer cell line Cell Culture Techniques Cell membrane Cell model Cell physiology Cells Centers of Research Excellence Characteristics Clinical Complex Confocal Microscopy Development Disease ECM receptor Excision Extracellular Matrix FRAP1 gene Foundations Functional disorder Genetic Goals Hyaluronic Acid Investigation Knowledge Link Malignant neoplasm of cervix uteri Mediating Modeling Molecular Movement Mutation Nerve Degeneration Neurodegenerative Disorders Organelles Outcome Parkinson Disease Pathway interactions Pharmacology Phase Phenotype Physiology Positioning Attribute Pre-Clinical Model Predisposition Process Proteins Proto-Oncogene Proteins c-akt Reporting Repression Research Role Signal Transduction Substantia nigra structure System Testing Therapeutic United States National Institutes of Health Work alpha synuclein base combat disease-causing mutation dopaminergic neuron experience improved insight macromolecule motor disorder motor symptom mutant neuron loss protein aggregation protein complex receptor symptom treatment therapy development trafficking transcriptome transcriptome sequencing

项目摘要

Project Summary - Morrison Parkinson’s disease (PD) is the most common motor disease in the USA. The primary clinical motor symptoms of PD result from loss of dopaminergic (DA) neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. Autophagy is a cellular process responsible for degradation of organelles, macromolecules, and protein aggregates. In PD, characteristic toxic protein aggregates of primarily alpha- synuclein are believed to be substrates for autophagic removal and clearance by autophagy improves preclinical model outcomes. Therefore, modulation of autophagy may be an effective strategy to combat PD. Recently, a PD-causing mutation in VPS35 (D620N) was reported to block autophagy. However, preliminary investigation by other groups into a causal mechanism was limited to canonical VPS35 protein interactors in a cervical cancer cell line. To overcome these limitations, we performed an unbiased screen using RNA sequencing (RNA seq) to identify key pathways affected in a widely used cellular model of PD. We have identified alterations indicative of perturbed extracellular matrix (ECM)-receptor interaction as well as aberrant AKT signaling, a downstream pathway known to regulate the induction of autophagy. Hyaluronic acid (HA) is the major component of brain ECM and signals via CD44, an ECM receptor identified as a top hit by our RNA Seq screen, to the autophagy regulating AKT-mTOR pathway, making this axis a prime candidate for mediating the VPS35 D620N autophagy blockade. Furthermore, VPS35’s well-established role in the retromer complex, a protein complex that directs plasma membrane receptor trafficking, suggests that altered trafficking of CD44 by the VPS35 mutant may be responsible for the observed alteration of AKT pathway activation and the subsequent repression of autophagy. The central hypothesis of this proposal is that VPS35 D620N blocks autophagy through dysregulated hyaluronic acid-CD44 signaling by altered trafficking of CD44. We propose testing our hypothesis by examining HA-CD44-AKT pathway activation in VPS35 mutant expressing cells; validating the importance of this pathway by genetic and pharmacological rescue of the mutant phenotype; and assessing whether aberrant CD44 activation leads to increased neuronal loss. Whether perturbed CD44 trafficking by VPS35 D620N underlies altered signaling will be determined.

项目摘要-摩理臣