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Investigation of cellular factors involved in yeast prion appearance

酵母朊病毒出现相关细胞因素的研究

基本信息

批准号：
8626550
负责人：
ANITA L. MANOGARAN
金额：
$ 34.31万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8626550
关键词：
Actins Address Affect Alzheimer&apos s Disease Appearance Biological Models Bovine Spongiform Encephalopathy Cattle Cells Commit Creutzfeldt-Jakob Syndrome Critical Thinking Cytoskeleton Deposition Development Disease Etiology Event Exposure to Gene Deletion Genes Goals Huntington Disease Investigation Lead Link Mediating Mentorship Morphology Neurodegenerative Disorders Parkinson Disease Pathway interactions Phase Play Prion Diseases Prions Process Protein Structure Initiative Proteins Reporting Research Role Saccharomyces cerevisiae Scaffolding Protein Science Scientist Site Staging Students System Testing Therapeutic Training Universities Vacuole Work Writing Yeasts actin 2 career daughter cell depolymerization design experience fusion gene innovation insight interest mutant novel particle polymerization prevent protein aggregation protein misfolding public health relevance skills therapy development transmission process undergraduate research undergraduate student yeast prion

项目摘要

Project Summary/Abstract: Many neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and Prion disease, are associated with protein misfolding. In each of these diseases, an endogenous protein misfolds and further converts the normal protein to the misfolded form. How the cellular milieu contributes to the misfolding of these proteins remains unclear. Our interests lie in understanding the cellular mechanisms that contribute to the development of these diseases. We will use Yeast prions as an experimental system to understand the different stages of prion formation. Our previous work was the first to show that two classes of genes affect prion formation at different steps. One class of genes is involved in the initial misfolding phases that lead to aggregation of the protein, whereas the other class is important in later steps of prion formation, which includes the transmission of newly misfolded aggregates to daughter cells. These genes encode proteins that are involved in actin polymerization and appear to be required to maintain normal vacuolar morphology. The focus of this project will specifically address how actin polymerization and the vacuole impact the multistep process of prion formation. In specific aim 1, we will focus on one of our genes, BEM1, which encodes for a scaffold protein involved in actin polymerization at the bud site and the vacuole. We will test our hypothesis that Bem1p mediated actin networks aid in the transmission of prion particles to the daughter cell. Aim 2 will investigate how perturbations in vacuole morphology associated with our deletions impacts the integrity of the insoluble protein deposit, a site associated with newly formed prion particles. In our last aim, we will investigate how one of our deletions, vps5, affects the formation of the newly misfolded prion protein. Together, the specific aims will dissect the role that actin networks and the vacuole play in prion formation.

项目概要/摘要：许多神经退行性疾病，如阿尔茨海默氏症、帕金森氏症、亨廷顿氏症和朊病毒病，与蛋白质错误折叠有关。在这些疾病中的每一种中，内源性蛋白质错误折叠并进一步将正常蛋白质转化为错误折叠的形式。细胞环境如何导致细胞的错误折叠这些蛋白质仍不清楚。我们的兴趣在于了解细胞机制，有助于这些疾病的发展。我们将使用酵母朊病毒作为一个实验系统，以了解朊病毒形成的不同阶段我们之前的工作首次表明，两类基因影响朊病毒形成的不同阶段。一类基因参与了最初的错误折叠阶段，导致蛋白质的聚集，而另一类在朊病毒形成的后期步骤中很重要，包括新错误折叠的聚集体向子细胞的传递。这些基因编码的蛋白质参与肌动蛋白聚合，似乎需要维持正常的液泡形态。重点本项目的第一部分将专门讨论肌动蛋白聚合和液泡如何影响多步骤过程朊病毒的形成在具体目标1中，我们将重点关注我们的基因之一BEM 1，它编码支架在芽部位和液泡参与肌动蛋白聚合的蛋白质。我们将测试我们的假设， Bem 1 p介导的肌动蛋白网络有助于朊病毒颗粒向子细胞的传递。目标2将研究与我们的缺失相关的液泡形态学的扰动如何影响细胞的完整性。不溶性蛋白质存款，与新形成的朊病毒颗粒相关的位点。在我们最后的目标，我们将研究我们的一个缺失，vps 5，如何影响新的错误折叠朊病毒蛋白的形成。这些特定的目标将一起剖析肌动蛋白网络和空泡在朊病毒形成中所起的作用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

De novo [PSI +] prion formation involves multiple pathways to form infectious oligomers.

[PSI]朊病毒从头形成涉及形成感染性寡聚体的多种途径。

DOI：
10.1038/s41598-017-00135-6
发表时间：
2017
期刊：
Scientific reports
影响因子：
4.6
作者：
Sharma,Jaya;Wisniewski,BrettT;Paulson,Emily;Obaoye,JoannaO;Merrill,StephenJ;Manogaran,AnitaL
通讯作者：
Manogaran,AnitaL

Cytoduction and Plasmiduction in Yeast.

酵母中的细胞诱导和质粒诱导。

DOI：
10.21769/bioprotoc.4146
发表时间：
2021
期刊：
Bio-protocol
影响因子：
0.8
作者：
Dorweiler,JaneE;Manogaran,AnitaL
通讯作者：
Manogaran,AnitaL

The actin cytoskeletal network plays a role in yeast prion transmission and contributes to prion stability.

DOI：
10.1111/mmi.14528
发表时间：
2020-09
期刊：
Molecular microbiology
影响因子：
3.6
作者：
Dorweiler JE;Oddo MJ;Lyke DR;Reilly JA;Wisniewski BT;Davis EE;Kuborn AM;Merrill SJ;Manogaran AL
通讯作者：
Manogaran AL

Toxicity and infectivity: insights from de novo prion formation.

毒性和感染力：从头形成的见解。