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Protein Aggregation and Inflammasome Signaling in Manganese Neurotoxicity

锰神经毒性中的蛋白质聚集和炎症小体信号转导

基本信息

批准号：
9275981
负责人：
Anumantha Gounder Kanthasamy
金额：
$ 32.89万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275981
关键词：
Address Affinity Agreement Alzheimer&apos s Disease Animal Model Astrocytes Binding Cell Culture Techniques Cells Chronic Complex Disease Encephalitis Endosomes Environment Functional disorder Goals Human Impairment Inflammasome Inflammatory Response Interleukin-1 beta Intervention Knockout Mice Link Manganese Mediating Metal Binding Site Metal exposure Metals Microglia Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Outcome Parkinson Disease Pathogenesis Pathologic Pathway interactions Play Process Protein Sortings Proteins Recycling Research Role Sampling Signal Transduction Small Interfering RNA Sorting - Cell Movement Testing Transgenic Mice Up-Regulation Vesicle alpha synuclein brain tissue chronic neurologic disease divalent metal exosome extracellular genetic approach in vivo insight nervous system disorder neuroinflammation neuron loss neurotoxicity novel prion-like protein E protein aggregate protein aggregation protein complex public health relevance response trafficking

项目摘要

DESCRIPTION (provided by applicant): Metal exposure has increasingly been recognized as a potential environmental contributor to chronic neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD). Chronic manganese (Mn) exposure has been implicated in Parkinson's-like neurological conditions in humans. Protein aggregation and its prion-like propagation are now considered the central pathophysiological mechanisms of many neurodegenerative diseases collectively known as proteinopathies. However, the role of metals in protein aggregation and the neurotoxicological mechanisms that drive degenerative processes are not well understood. α-Synuclein (αSyn) protein aggregation has been implicated in PD, and this protein features multiple divalent metal-binding motifs that have been suggested to play a role in αSyn's fibrillization and neurotoxicity. Since Mn shows affinity to the metal binding sites in αSyn, we have examined the effect of Mn on αSyn in neuronal models. Interestingly, we found that αSyn protected against Mn-induced neurotoxicity during early stages of Mn exposure, but prolonged Mn exposure promoted αSyn aggregation. In agreement with the emerging concept that aggregated proteins propagate cell-to-cell via exosomal release, we also observed enhanced release of exosomes containing αSyn into the extracellular environment during Mn exposure. Thus, our exciting finding of Mn-induced αSyn aggregation and release of exosomes with αSyn cargo prompts us to further characterize the cellular and molecular mechanisms of neurodegenerative processes in Mn neurotoxicity. Our proposal will test the novel hypothesis that Mn exposure promotes αSyn misfiling and impairs intracellular αSyn trafficking, thereby increasing the formation and release of exosomes containing αSyn protein aggregates, which subsequently trigger microglial activation through the NLRP3 inflammasome pathway in a PKCδ-dependent manner. Sustained activation of the PKCδ-dependent NLRP3 inflammasome pathway contributes to Mn neurotoxicity. Specific objectives of the proposal are: (i) to characterize the cellular mechanism of Mn-induced impairment in endosomal trafficking, retromer dysfunction and exosome release in cell culture and animal models of Mn neurotoxicity, (ii) to determine NLRP2/3 inflammasome neuroinflammatory signaling in microglia and astrocytes triggered by Mn-induced exosomal αSyn aggregates and to characterize the proinflammatory regulatory function of PKCδ in NLRP2/3 inflammasome activation in Mn neurotoxicity, and (iii), to examine the role of PKCδ in mediating the exosomal αSyn aggregate-induced proinflammatory response in animal models of Mn neurotoxicity and to confirm the presence of αSyn protein aggregation in Mn-exposed human brain tissues. Our integrated cellular and molecular approach to unraveling the formation and release of exosomal αSyn aggregates and their functional consequences on neuroinflammatory signaling in manganese metal neurotoxicity will provide novel mechanistic insights into environmentally-linked neurodegenerative disorders.