• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Characterization of Wild Type and Mutant Atp13a2 Proteins Linked to Parkinson's Disease

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Ugolino_umaryland_0373D_10237.pdf
    Size:
    4.729Mb
    Format:
    PDF
    Download
    Author
    Ugolino, Janet
    Advisor
    Monteiro, Mervyn J.
    Date
    2011
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor at rest, postural instability, bradykinesia, and rigidity. Mutations in ATP13A2 have been linked to the development of Kufor-Rakeb syndrome (KRS), a juvenile-onset form of parkinsonism with dementia. The ATP13A2gene is alternatively spliced to produce three Atp13a2 protein isoforms. However, little is known about the function of Atp13a2 in the cell or how mutations in the gene cause disease. It has been reported that wild type (wt) proteins localize to lysosomes while mutant Atp13a2<superscript>Isoform-1</superscript> proteins are retained in the endoplasmic reticulum (ER) and rapidly degraded by the proteasome. These findings suggest mutant Atp13a2Isoform-1 proteins are eliminated by the ER-associated degradation (ERAD) pathway, the process by which misfolded proteins are retro-translocated from the ER to the cytoplasm for degradation by the proteasome, although direct evidence for this was not demonstrated. We approached this question by examining protein turnover after disrupting specific components of the ERAD pathway. Interference of ERAD by either inhibition of the proteasome, or expression of a dominant negative p97/VCP QQ mutant, or knockdown of erasin, slowed the turnover of mutant Atp13a2<superscript>Isoform-1</superscript>proteins. Furthermore, immunoprecipitation assays revealed Atp13a2 proteins are ubiquitinated, as expected. Functional studies in HeLa cells indicated that overexpression of the wild type Atp13a2<superscript>Isoform-1</superscript> protein is cytoprotective against agents that cause ER stress, manganese toxicity, and starvation. Similar studies of the Atp13a2<superscript>Isoform-3</superscript> proteins revealed surprising differences. In contrast to the Atp13a2<superscript>Isoform-1</superscript> protein, wild type Atp13a2<superscript>Isoform-3</superscript> was found to localize to the ER, be rapidly degraded by the proteasome, and its overexpression was found to be cytotoxic. These results provide new insight into functional differences between wild type and mutant Atp13a2 proteins, which are likely to be important in understanding the pathogenicity of Atp13a2 proteins in PD.
    Description
    University of Maryland in Baltimore. Biochemistry. Ph.D. 2011
    Keyword
    Parkinson Disease
    Proton-Translocating ATPases--genetics
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/761
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.