The Cell Biology of Neurodegeneration Caused by the Prion Protein

朊病毒蛋白引起的神经变性的细胞生物学

• 批准号: 8351218
• 负责人: Ramanujan S Hegde
• 金额: $ 37.32万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8351218
• 关键词: Anabolism; Animals; Biogenesis; Biological Models; Bovine Spongiform Encephalopathy; Cell Culture Techniques; Cell Death; Cells; Cellular biology; Cessation of life; Cytosol; Defect; Disease; Endoplasmic Reticulum; Event; Functional disorder; Future; Genes; Goals; Golgi Apparatus; Inherited; Lead; Light; Locales; Location; Lysosomes; Mediating; Membrane Glycoproteins; Membrane Proteins; Metabolism; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Pathway interactions; Prion Diseases; Prions; Process; Property; Protein Biosynthesis; Proteins; Quality Control; Recruitment Activity; Site; Therapeutic Intervention; Transgenic Mice; base; cytotoxic; disease-causing mutation; in vivo; interest; mutant; neurodegenerative phenotype; neuron loss; protein aggregate; protein metabolism; protein misfolding; secretory protein; trafficking

The prion protein (PrP) is a widely expressed and highly conserved cell surface glycoprotein of uncertain function. Aberrant metabolism of PrP is responsible for a variety of neurodegenerative diseases in both people and animals. These diseases include the transmissible 'prion diseases' such as bovine spongiform encephalopathy, as well as inheritable neurodegenerative diseases caused by mutations in the PrP gene. In neither case is the pathway(s) leading to cell death and neuronal damage understood. The overall goal of this project is to define the pathways of PrP-mediated neurodegeneration. To achieve this goal, we are studying the molecular pathways of PrP biosynthesis, intracellular trafficking, metabolism, and degradation. A quantitative analyses of these events are expected to shed light on how the various inherited mutations in PrP influence its biosynthesis or metabolism in a manner that leads the cellular dysfunction. Our analysis suggests that at least two cytotoxic forms of PrP (termed CtmPrP and cyPrP) are during the initial translocation of PrP into the endoplasmic reticulum (ER). Transgenic mice have now been created to determine whether CtmPrP-mediated neurodegeneration and cyPrP-mediated neurodegeneration can be averted in vivo by modulating this newly discovered step during PrP biogenesis. We are also investigating the pathways by which the various forms of PrP are normally metabolized by the cell to determine whether modulation of these events are involved in the progression of neurodegeneration. It is anticipated that a combination of defects in biosynthesis and/or clearance of certain forms of PrP collaborate to eventually cause neuronal dysfunction and death. Conversely, manipulation of these events may be able to slow or reverse the neurodegenerative process in these diseases. In parallel, we are also performing a systematic analysis of the biosynthesis, trafficking, and metabolism of disease-associated PrP mutants. The aim of these studies is to identify precisely the cellular locale and mechanism of PrP misfolding that initiates the disease process. Our current analyses have found that for a large number of mutants, misfolded PrP is found in a post-ER location, from where it is routed to lysosomes for degradation. This observation is notable because it suggests that the misfolded PrP species have somehow escaped the normal cellular quality control mechanisms in the ER, and instead use yet unidentified quality control pathways in the Golgi. These new pathways of quality control are now being investigated. In parallel studies, the downstream consequences of PrP misfolding and aggregation are being studied to identify the mechanism by which these events lead to cellular dysfunction. We have now found that these aggregates recruit various cellular factors, therby depleting their functional availability. One such factor is of particular importance because its disruption in mice leads directly to a neurodegenerative phenotype reminiscent of diseases caused by PrP. And finally, we are investigating the general properties of protein aggregates, which are associated with a wide range of diseases. We have discovered the the presence of cytosolic aggregates can significantly influence the pathways of normal cellular quality control. In one specific example, we have found that aggregates influence the fate of mislocalized secretory and membrane proteins. Rather than being rapidly degraded, the presence of aggregates causes these proteins to remain undegraded in the cytosol. This leads to their co-aggregation, facilitating the propogation of the existing aggregates and causing cell death. The molecular basis of this phenomenon is now being investigated.

朊病毒蛋白（PrP）是一种广泛表达且高度保守的细胞表面糖蛋白，功能不确定。在人和动物中，PrP的异常代谢是多种神经退行性疾病的原因。这些疾病包括传染性“朊病毒疾病”，如牛海绵状脑病，以及由PrP基因突变引起的遗传性神经退行性疾病。在这两种情况下，导致细胞死亡和神经元损伤的途径都不清楚。该项目的总体目标是确定prp介导的神经退行性变的途径。为了实现这一目标，我们正在研究PrP生物合成、细胞内运输、代谢和降解的分子途径。对这些事件的定量分析有望揭示PrP中各种遗传突变如何以导致细胞功能障碍的方式影响其生物合成或代谢。

项目成果

Cytosolic aggregates perturb the degradation of nontranslocated secretory and membrane proteins.

• DOI: 10.1091/mbc.e10-07-0638
• 发表时间: 2011-05-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Chakrabarti O;Rane NS;Hegde RS
• 通讯作者: Hegde RS

Functional depletion of mahogunin by cytosolically exposed prion protein contributes to neurodegeneration.

• DOI: 10.1016/j.cell.2009.03.042
• 发表时间: 2009-06-12
• 期刊: Cell
• 影响因子: 64.5
• 作者: Chakrabarti O;Hegde RS
• 通讯作者: Hegde RS

Compartment-restricted biotinylation reveals novel features of prion protein metabolism in vivo.

• DOI: 10.1091/mbc.e10-09-0742
• 发表时间: 2010-12
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Emerman AB;Zhang ZR;Chakrabarti O;Hegde RS
• 通讯作者: Hegde RS

Selective processing and metabolism of disease-causing mutant prion proteins.

• DOI: 10.1371/journal.ppat.1000479
• 发表时间: 2009-06
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Ashok A;Hegde RS
• 通讯作者: Hegde RS

Reduced translocation of nascent prion protein during ER stress contributes to neurodegeneration.

在ER应激期间，新生prion蛋白的易位降低会导致神经退行性。

• DOI: 10.1016/j.devcel.2008.06.015
• 发表时间: 2008-09
• 期刊: DEVELOPMENTAL CELL
• 影响因子: 11.8
• 作者: Rane, Neena S.;Kang, Sang-Wook;Chakrabarti, Oishee;Feigenbaum, Lionel;Hegde, Ramanujan S.
• 通讯作者: Hegde, Ramanujan S.