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生和发展的基础。尽管这些疾病的临床阶段以神经元死亡为特征，但细胞周围的功能障碍，尤其是突触的功能障碍，可能发生得更早。我们发现与帕金森病（PD）有关的环境毒素（如农药）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），这是细胞内降解错误折叠、氧化或不再需要的蛋白质的主要途径。此外，一些与PD相关的基因编码了与UPS相关的蛋白质。在PD中，路易小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，我们提出神经元的蛋白酶体功能障碍损害突触功能，并作为神经元变性的早期指标。除了蛋白质降解外，线粒体功能似乎在PD中受损。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相关的农药抑制线粒体电子传递链。线粒体功能受损将降低细胞ATP水平，增加活性氧（ROS），从而氧化蛋白质。UPS也能降解氧化蛋白，需要ATP才能正常工作。因此，对于直接影响线粒体功能的基因和毒素，UPS是PD病因学的潜在中心靶点。我们认为UPS功能障碍引发的突触传递变化是神经元易感性的早期指标。因此，突触功能提供了一种有用的检测方法，用于检测神经退行性疾病（如PD）的遗传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。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，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动物模型与对照组神经元突触传递的影响，并辨别影响是更严重，发生在不同浓度还是仅仅以不同的方式发生。这项工作直接测试了基因和环境因素在PD病因学中的相互作用。我们的实验是基于神经退行性疾病中发现的基因突变与环境毒素相互作用以影响突触功能的假设。我们进一步提出突触功能障碍是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。所开发的实验范式将有助于建立农药毒性筛选工具和与神经退行性疾病相关的治疗干预措施。

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.