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

描述(由申请人提供)：环境风险因素以及遗传易感性是大多数神经退行性疾病发展和进展的基础。虽然神经元死亡是许多这些疾病的临床阶段的特征，但细胞外周功能障碍，特别是突触功能障碍，可能发生得更早。我们发现，与帕金森病(PD)有关的环境毒素，如杀虫剂，会迅速影响突触传递和突触可塑性。这些毒素中的许多也会影响泛素蛋白酶体系统(UPS)，UPS是降解错误折叠、氧化或不再需要的蛋白质的主要细胞内途径。此外，几个与帕金森病相关的基因编码了参与UPS的蛋白质。在帕金森病中，路易体中蛋白质聚集体的积累表明蛋白质加工和降解的缺陷。因此，我们认为，神经元中的蛋白酶体功能障碍损害了突触功能，并可作为神经元变性的早期指标。除了蛋白质降解，帕金森病患者的线粒体功能似乎也受到了影响。有趣的是，一些与PD相关的基因编码线粒体蛋白质，一些与PD相关的杀虫剂抑制线粒体电子传输链。线粒体功能受损会降低细胞的ATP水平，增加活性氧物种(ROS)，从而增加氧化蛋白。UPS也能降解氧化蛋白质，需要ATP才能正常发挥作用。因此，即使对于直接影响线粒体功能的基因和毒素，UPS也是帕金森病病因学中潜在的中心靶点。我们认为，由UPS功能障碍引发的突触传递的变化是神经元脆弱性的早期指标。因此，突触功能为测试遗传和环境因素之间的相互作用提供了一个有用的测试方法，这些因素是导致神经退行性疾病(如帕金森病)的基础。帕金森病是一种进行性疾病。生理变化必须先于临床症状。帕金森病的遗传动物模型同样显示出进行性的行为和生理缺陷，而且--就像人类疾病一样--在生命早期没有明显的缺陷。我们的研究将确定环境毒素对PD动物模型神经元突触传递的影响与对照组相比，并区分影响是更严重，发生在不同浓度还是只是以不同的方式发挥作用。这项工作直接测试了帕金森病病因中基因和环境因素的相互作用。我们的实验是基于这样的假设，即在神经退行性疾病中发现的基因突变与环境毒素相互作用，影响突触功能。我们进一步建议将突触功能障碍作为帕金森病的早期征兆。我们的实验将为确定帕金森病和其他神经退行性疾病的潜在环境和遗传风险因素奠定基础。开发的实验范例将有助于建立与神经退行性疾病相关的杀虫剂毒性和治疗干预的筛查工具。 公共卫生相关性：遗传易感性和环境因素是大多数神经退行性疾病发展和进展的基础，如帕金森氏病(PD)。这项拨款申请提出了一项假设，即突触神经元之间的通信受到农药等环境毒素的影响，与帕金森病相关的特定基因的突变与这些完全相同的途径相互作用，加剧了突触功能障碍。这些实验旨在阐明基因和环境之间的这种相互作用，并为突触功能改变可以在未来的研究中用作神经退行性疾病的农药毒性预测指标的想法找到支持。

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.