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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    The function of protein proline rich 7 (PRR7) in rodent forebrain

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    Date
    2015
    Author
    Kravchick, Dana O.
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    Abstract
    Neuronal stimulation regulates protein levels to alter synaptic function. Synaptic stimulation activates the Ubiquitin Proteasome System (UPS) to degrade proteins and balance immediate changes in protein levels. Dysfunction of the UPS is associated with neurodevelopmental and neurodegenerative disorders such as Angelman Syndrome and Alzheimer's disease. Identification of activity dependent regulators of the ubiquitin proteasome system (UPS) is crucial for understanding how neuronal function is altered in disorders where the UPS is disrupted. Previous work in our lab has identified PRR7 as a postsynaptic protein that also localized to neuronal nuclei. Since proteins with similar distribution pattern were identified as synapse-to-nucleus messengers (e.g. Jacob, NF-KB) I hypothesized that PRR7 could act in similar manner. For this purpose I studied PRR7 expression and function in rodent neurons. My work demonstrated that NMDAR (N-MethylD-Aspartate Receptor) activation alters PRR7 distribution between these compartments. Remarkably, characterization of PRR7 function in primary neurons revealed that it serves a unique role during neuronal stimulation by inhibiting the ubiquitination of the transcription factor c-Jun and enabling an increase in N-terminally phosphorylated c-Jun (phospho-cJun). Increase in phospho-c-Jun levels is associated with NMDA mediated excitotoxicity and has been reported in multiple neurodegenerative disorders and following episodes of ischemia and epileptic seizures. I show here that knockdown of PRR7 can attenuate NMDAR dependent excitotoxicity, whereas PRR7 overexpression triggers massive neuronal cell death. To conclude, this study identifies PRR7 as a novel player in NMDA dependent signaling to the nucleus to regulate c-Jun ubiquitination and mediate NMDA dependent excitotoxicity.
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    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3664437
    https://hdl.handle.net/20.500.12202/1557
    Citation
    Source: Dissertation Abstracts International, Volume: 77-03(E), Section: B.;Advisors: Bryen A. Jordan.
    *This is constructed from limited available data and may be imprecise.
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