Indicators of early neurodegeneration: gene-toxin interactions at the syanpse

早期神经退行性变的指标：突触处的基因-毒素相互作用

• 批准号: 7707066
• 负责人: FELIX E SCHWEIZER
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707066
• 关键词: Affect; Animal Model; Animals; Applications Grants; Behavioral; Biological Assay; Brain; Cells; Cessation of life; Clinical; Code; Communication; Degradation Pathway; Development; Disease; Electron Transport; Environment; Environmental Risk Factor; Etiology; Exposure to; Functional disorder; Future; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Health; Hippocampus (Brain); Hour; In Vitro; Lactones; Lewy Bodies; Life; Link; Long-Term Depression; Long-Term Potentiation; Mitochondria; Mitochondrial Proteins; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkin gene; Parkinson Disease; Pathway interactions; Pesticides; Physiological; Predisposition; Presynaptic Terminals; Process; Progressive Disease; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Reactive Oxygen Species; Reagent; Relative (related person); Rotenone; Screening procedure; Slice; Staging; Symptoms; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; System; Testing; Therapeutic Intervention; Toxic Environmental Substances; Toxin; Transgenic Model; Ubiquitin; Work; Ziram; alpha synuclein; base; design; gene interaction; genetic risk factor; human disease; lactacystin; mitochondrial dysfunction; multicatalytic endopeptidase complex; mutant; neuronal survival; neurotransmitter release; parkin gene/protein; pesticide poisoning; protein aggregate; protein degradation; public health relevance; research study; small hairpin RNA; synaptic function; tool; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Environmental risk factors as well as genetic predisposition underlie the development and progression of most neurodegenerative diseases. Although neuronal death characterizes the clinical stages of many of these diseases, dysfunction in the cell periphery, especially at the synapse, likely occur earlier. We find that environmental toxins such as pesticides that are implicated in Parkinson's disease (PD) rapidly affect synaptic transmission and synaptic plasticity. Many of these same toxins also affect the ubiquitin proteasome system (UPS), a major intracellular pathway for degradation of misfolded, oxidized or no-longer needed proteins. Further, several of the genes that have been linked to PD code for proteins involved in the UPS. In PD, the accumulation of protein aggregates in Lewy bodies points towards a deficit in protein processing and degradation. We therefore propose that proteasomal dysfunction in neurons compromises synaptic function and serves as an early indicator of neuronal degeneration. In addition to protein degradation, mitochondrial function appears compromised in PD. Interestingly, some PD-linked genes code for mitochondrial proteins and some pesticides linked to PD inhibit the mitochondrial electron transport chain. Compromised mitochondrial function will decrease cellular ATP levels and increases reactive oxygen species (ROS) and thus oxidized proteins. The UPS, which also degrades oxidized proteins, requires ATP for proper function. Thus, the UPS is a potential central target in the etiology of PD even for genes and toxins that directly affect mitochondrial function. We propose that changes in synaptic transmission triggered by UPS dysfunction represent an early indicator for neuronal vulnerability. Synaptic function thus offers a useful assay to test for the interaction between genetic and environmental factors underlying neurodegenerative diseases such as PD. PD is a progressive disease. Physiological alterations must precede clinical symptoms. Genetic animal models for PD similarly show progressive behavioral and physiological deficits and - like human disease - no deficits are evident early in life. Our studies will determine the impact of environmental toxins on synaptic transmission in neurons derived from PD animal models versus those from controls, and discern whether effects are more severe, occur at different concentrations or simply act in a different way. This work directly tests the interaction of genes and environmental factors in the etiology of PD. Our experiments are based on the hypothesis that genetic mutations found in neurodegenerative diseases interact with environmental toxins to affect synaptic function. We further propose synaptic dysfunction as an early sign of PD. Our experiments will lay the groundwork for identifying potential environmental and genetic risk factors for PD and other neurodegenerative diseases. The experimental paradigms developed will be useful in establishing a screening tool for the toxicity of pesticides and therapeutic interventions in relationship to neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Genetic predisposition and environmental factors underlie the development and progression of most neurodegenerative diseases such as Parkinson's disease (PD). This grant application proposes to test the hypothesis that communication between neurons at synapses is compromised by environmental toxins such as pesticides and that mutations in specific genes associated with PD interact with these very same pathways to exacerbate the synaptic dysfunction. The experiments are designed to elucidate this interaction between genes and the environment and to find support for the idea that alterations of synaptic function could be used in future studies as predictors of pesticide toxicity with respect to neurodegenerative diseases.

描述（由申请人提供）：环境风险因素以及遗传倾向是大多数神经退行性疾病的发展和进展。尽管神经元死亡是许多此类疾病的临床阶段的特征，但细胞周围功能障碍，尤其是在突触时，可能发生了早期。我们发现，与帕金森氏病（PD）有关的环境毒素（例如农药）迅速影响突触传播和突触可塑性。这些相同的毒素中的许多也会影响泛素蛋白酶体系统（UPS），这是降解错误折叠，氧化或无需蛋白质的主要细胞内途径。此外，几个与UPS涉及的蛋白质PD代码相关的基因。在PD中，路易体中蛋白质聚集体的积累表明蛋白质加工和降解的不足。因此，我们建议神经元中的蛋白酶体功能障碍会损害突触功能，并作为神经元变性的早期指标。除蛋白质降解外，线粒体功能在PD中似乎受到损害。有趣的是，某些针对线粒体蛋白的PD连锁基因代码和与PD相关的一些农药抑制了线粒体电子传输链。线粒体功能受损将降低细胞ATP水平，并增加活性氧（ROS），从而氧化蛋白质。 UPS也需要降解氧化蛋白，需要ATP才能正确功能。因此，即使对于直接影响线粒体功能的基因和毒素，UPS也是PD病因的潜在中心靶标。我们建议由UPS功能障碍触发的突触传播的变化代表了神经元脆弱性的早期指标。因此，突触功能提供了一种有用的测定法，以测试神经退行性疾病（如PD）的遗传因素和环境因素之间的相互作用。 PD是一种进行性疾病。生理改变必须先于临床症状。 PD的遗传动物模型类似地显示出渐进的行为和生理缺陷，并且像人类疾病一样 - 在生命的早期就没有明显的缺陷。我们的研究将确定环境毒素对来自PD动物模型的神经元与对照组的神经元的突触传播的影响，并辨别出效果是否更严重，以不同的浓度发生或简单地以不同的方式起作用。这项工作直接测试了PD病因中基因和环境因素的相互作用。我们的实验基于以下假设：神经退行性疾病中发现的遗传突变与环境毒素相互作用以影响突触功能。我们进一步提出突触功能障碍作为PD的早期迹象。我们的实验将为识别PD和其他神经退行性疾病的潜在环境和遗传危险因素奠定基础。开发的实验范例将有助于建立与神经退行性疾病有关的农药毒性和治疗干预措施的筛查工具。 公共卫生相关性：遗传倾向和环境因素是大多数神经退行性疾病（例如帕金森氏病）（PD）的发展和发展的基础。该赠款的应用建议测试以下假设：突触下神经元之间的通信受到农药等环境毒素的损害，并且与PD相关的特定基因中的突变与这些相同相同的途径相互作用，以加剧突触性功能障碍。该实验旨在阐明基因与环境之间的这种相互作用，并为以下想法寻求支持，即突触功能的改变可以在未来的研究中用作对神经退行性疾病的农药毒性的预测指标。