Mechanisms of Prion Misfolding

朊病毒错误折叠的机制

• 批准号: 8150030
• 负责人: PEDRO FERNANDEZ-FUNEZ
• 金额: $ 1.55万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150030
• 关键词: Binding; Biochemical; Creutzfeldt-Jakob Syndrome; Data; Disease; Drosophila genus; Endoplasmic Reticulum; Genes; Genetic; Goals; Hamsters; Heat-Shock Response; Human; In Vitro; Invertebrates; Mammalian Cell; Molecular; Molecular Chaperones; Molecular Conformation; Mus; Nerve Degeneration; Neuroblastoma; Neurons; Patients; Prion Diseases; Prions; Therapeutic; Transgenic Mice; base; fly; in vivo; killings; multicatalytic endopeptidase complex; prevent

Prion diseases are a group of aggressive, lethal and incurable neurodegenerative disorders. The hallmark pathological event in these maladies is the misfolding, aggregation and brain deposition of ¿scrapie¿ Prion protein (PrPSc), which leads to spongiform degeneration of brain neurons. Unfortunately, a major gap exists in our understanding of how the conformational conversion of PrP ultimately kills neurons. Recent in vitro studies suggest that molecular chaperones may be key factors mediating PrP conversion and neuronal dysfunction. However, the functional relevance of this finding is unknown. My central hypothesis is that targeted expression of molecular chaperones can suppress PrP misfolding and PrP-mediated neurodegeneration. To that end, I created a novel and powerful Drosophila model of sporadic prion disease in which wild type PrP from Hamster converts into PrPSc¿like conformations and causes spongiform degeneration. Supporting my hypothesis, human Hsp70 prevents PrP misfolding and protects against PrP-dependent neurotoxicity in transgenic flies. The overall goal of this project is to define the role of molecular chaperones in PrP misfolding by a multidisciplinary approach that combines the power of Drosophila genetics with mammalian cellular systems and mice. My specific aims are: 1) Genetic, biochemical and pharmacological approaches to study Hsp70 protection against PrP misfolding and neurotoxicity in Drosophila; 2) Determination of the ability of the Unfolded Protein Response components XBP1s and Grp58 to suppress PrP misfolding and neurotoxicity in Drosophila; 3) Role of molecular chaperones in prion replication in simplified mammalian systems, and 4) Potential therapeutic role of Hsp70 in mouse models of prion diseases. I anticipate that our studies will contribute to better understand the molecular basis underlying PrP conversion. In addition, by exploring the role of chaperone-inducing compounds in flies and mice, I may discover effective and innovative therapeutic interventions for treating these devastating and yet incurable diseases.

病毒疾病是一组侵略性，致命和无法治愈的神经退行性疾病。这些疾病中的标志性病理事件是ccrapie` prion蛋白（PRPSC）的错误折叠，聚集和脑沉积，这导致了脑神经元的赞助变性。不幸的是，我们对PRP的构象转换如何最终杀死神经元的理解存在一个主要差距。最近的体外研究 表明分子链烷可能是介导PRP转化和神经元功能障碍的关键因素。但是，该发现的功能相关性尚不清楚。我的中心假设是，分子链烷的靶向表达可以抑制PRP杂后和PRP介导的神经变性。为此，我创建了一种新颖而强大的果蝇模型的零星prion病模型，其中野生型PRP 从仓鼠转化为PRPSC。例如会议，并导致赞助变性。支持我的假设，人类HSP70可防止PRP错误折叠，并预防转基因蝇中PRP依赖性神经毒性。该项目的总体目标是通过多学科方法来定义分子伴侣在PRP中的作用 系统和鼠标。我的具体目的是：1）研究HSP70防止PRP错误折叠和果蝇神经毒性的遗传，生化和药物方法； 2）确定展开的蛋白质反应成分XBP1和GRP58抑制果蝇中PRP错误折叠和神经毒性的能力； 3）分子伴侣在简化哺乳动物系统中的prion复制中的作用，4） Hsp70在主要疾病的小鼠模型中的潜在治疗作用。我预计我们的研究将有助于更好地理解分子基础PRP转换。此外，通过探索伴侣蛋白诱导的化合物在苍蝇和小鼠中的作用，我可能会发现有效且创新的治疗干预措施，以治疗这些毁灭性且无法治愈的疾病。

项目成果

Modeling the complex pathology of Alzheimer's disease in Drosophila.

• DOI: 10.1016/j.expneurol.2015.05.013
• 发表时间: 2015-12
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Fernandez-Funez P;de Mena L;Rincon-Limas DE
• 通讯作者: Rincon-Limas DE

Anti-Aβ single-chain variable fragment antibodies restore memory acquisition in a Drosophila model of Alzheimer's disease.

• DOI: 10.1038/s41598-017-11594-2
• 发表时间: 2017-09-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Martin-Peña A;Rincon-Limas DE;Fernandez-Funez P
• 通讯作者: Fernandez-Funez P

Activation of JNK signaling mediates amyloid-ß-dependent cell death.

• DOI: 10.1371/journal.pone.0024361
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Tare M;Modi RM;Nainaparampil JJ;Puli OR;Bedi S;Fernandez-Funez P;Kango-Singh M;Singh A
• 通讯作者: Singh A

Polar substitutions in helix 3 of the prion protein produce transmembrane isoforms that disturb vesicle trafficking.

• DOI: 10.1093/hmg/ddt276
• 发表时间: 2013-11
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: J. Sanchez-Garcia;Daniela Arbeláez;K. Jensen;D. Rincon-Limas;P. Fernandez-Funez

A single amino acid (Asp159) from the dog prion protein suppresses the toxicity of the mouse prion protein in Drosophila.

• DOI: 10.1016/j.nbd.2016.07.025
• 发表时间: 2016-11
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Sanchez-Garcia, J.;Jensen, K.;Zhang, Y.;Rincon-Limas, D. E.;Fernandez-Funez, P.
• 通讯作者: Fernandez-Funez, P.