Animal Disaggregases and Amyloid Contributions to Early Development

包括阿尔茨海默氏病、帕金森氏病、ALS和亨廷顿病在内的神经退行性疾病构成了严重的医疗保健和社会挑战，在美国估计患病率为700万例。这些是蛋白质错误折叠疾病，其中环境、压力和老化的组合触发正常蛋白质转化为称为淀粉样蛋白的非功能性和有害的聚集体，其随时间的积累导致神经元死亡。治疗有毒聚集体的一个被忽视但关键的挑战是，蛋白质聚集也是适应性的，具有重要的生物功能，如长期记忆，肽激素的储存和动物中的黑色素聚合。现在还清楚的是，蛋白质聚集体在正常动物发育中广泛存在，并且在引入能够解开聚集体的非天然蛋白质时它们的错误调节导致发育缺陷。这项建议的目的是表征淀粉样蛋白聚集体的存在和作用，在早期发展和调查他们的监管一类新的分子伴侣，这可能是关键的动物发育过程中的聚集体加工。了解发育重要的聚集体的调节将导致洞察聚集体为基础的病理和新的发展机制的战略，利用功能蛋白质聚集体来调节细胞命运的规范。更广泛的影响活动包括开发新的基于探究的学习活动，以增加STEM领域的性别和少数民族多样性，并实施每年为期6周的培训计划大使（ATP），以培训一个~ 10名本科生在科学传播，使他们能够领导加强部门图尔斯参观访问潜在的学生和他们的家人。支持动物群体是早期发育的重要组成部分的假设。本建议的目的是表征淀粉样蛋白聚集体的存在和作用，在早期发展和调查他们的调节ABCF蛋白，以前已被证明影响聚集报告和本地朊病毒在酵母，在体外变性蛋白的再溶解，和淀粉样蛋白在动物发育过程中的加工。淀粉样蛋白聚集体在早期发育中广泛存在的发现促使人们以新的方式思考和研究发育中的淀粉样蛋白聚集体。该方案充分利用了C. elegans和S.酿酒酵母中的ABCF蛋白来测试以下假设：ABCF蛋白是新颖的、高度保守的并且迄今未被充分认识的解聚物，其调节酵母中的蛋白质稳态和动物中的无膜细胞器形成，从而以细胞命运特异性方式控制可溶性功能性蛋白质组。目的1检测ABCF基因在动物发育过程中聚集的组织和细胞类型特异性中的作用。目的2描述了ABCF在蠕虫和酵母中调节RNA加工（P）体成分聚集的作用，目的3确定了ABCF蛋白作为伴侣的作用机制。总之，这些目标描述了一个全面的检查淀粉样蛋白和他们的专用disaggregas作为新的监管机构的关键事件在早期动物发育，包括存储，繁殖和分布的母体和合子合成的蛋白质，可以根据需要释放。 该项目由内部监督办公室/开发系统集群和促进竞争研究既定计划（EPSCoR）共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Neurodegenerative diseases including Alzheimer’s, Parkinson’s, ALS, and Huntington’s disease pose a serious healthcare and societal challenge with an estimated prevalence of 7 million cases in the US. These are protein misfolding diseases in which the combination of environment, stress, and aging trigger the conversion of normal proteins into non-functional and deleterious aggregates known as amyloids whose accumulation over time leads to neuronal death. One overlooked but critical challenge for treating toxic aggregates is that protein aggregation is also adaptive, serving vital biological functions such as long-term memory, storage of peptide hormones, and melanin polymerization in animals. It is now also clear that protein aggregates are widespread in normal animal development and their mis-regulation upon introducing non-native proteins capable of disentangling aggregates results in developmental defects. The objective of this proposal is to characterize the presence and role of amyloid aggregates during early development and to investigate their regulation by a novel class of chaperones which may be key to aggregate processing during animal development. Understanding the regulation of developmentally important aggregates will lead to insights into aggregate-based pathologies and novel developmental mechanistic strategies utilizing functional protein aggregates to regulate cell fate specification. The Broader Impact activities include developing new inquiry-based learning activities to increase gender and minority diversity in STEM fields and implementing an annual 6-week Ambassador in Training Program (ATP) to train a class of ~10 undergraduates in science communication so they can lead enhanced Departmental tours to visiting potential students and their families.The PIs recently identified multiple specific amyloid bodies during the early stages of animal development supporting the hypothesis that animal aggregates are an important component of early development. The objective of this proposal is to characterize the presence and role of amyloid aggregates during early development and to investigate their regulation by the ABCF proteins which have been previously demonstrated to affect aggregation reporters and native prions in yeast, resolubilization of denatured proteins in vitro, and amyloid processing during animal development. The finding that amyloid aggregates are widespread in early development prompted a new way of thinking about and investigating amyloid aggregates in development. This proposal capitalizes on the complementary and synergistic experimental advantages of C. elegans and S. cerevisiae to test the hypothesis that ABCF proteins are novel, well-conserved and heretofore underappreciated disaggregases that regulate proteostasis in yeast and membrane-less organelle formation in animals, thereby controlling the soluble, functional proteome in a cell fate-specific manner. Aim 1 tests the role of ABCF genes in tissue and cell type specificity of aggregation during animal development. Aim 2 characterizes the role of ABCF in regulating RNA processing (P) body constituent aggregation in worms and yeast, and Aim 3 determines the mechanism of action of Abcf proteins as chaperones. Together, these aims describe a comprehensive examination of how amyloids and their dedicated disaggregases serve as novel regulators of key events in early animal development including storage, propagation, and distribution of maternal and zygotically synthesized proteins that can be released as required. This project is jointly funded by IOS/Developmental Systems Cluster and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.