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    Investigating Proteolytic Processing of Ataxin 2, a Neurodegenerative Disease Associated Protein

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    Name:
    Chitre Thesis 091822.pdf
    Embargo:
    2023-09-18
    Size:
    3.603Mb
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    Authors
    Chitre, Monika
    Student Authors
    Monika Chitre
    Faculty Advisor
    Patrick Emery
    Academic Program
    Interdisciplinary
    UMass Chan Affiliations
    Neurobiology
    Emery Lab
    Document Type
    Doctoral Dissertation
    Publication Date
    2022-08-08
    Keywords
    neurodegeneration
    proteolysis
    ataxin 2
    
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    Abstract
    Ataxin 2 (ATXN2) is a ubiquitously expressed mRNA binding protein involved in the development and progression of spinocerebellar ataxia 2 (SCA2) and amyotrophic lateral sclerosis (ALS). In the context of both neurodegenerative diseases, its N-terminal polyglutamine (polyQ) domain is mutated and expanded in length. Several other polyQ proteins, such as huntingtin (Htt), ataxin 3 (ATXN3), and ataxin 7 (ATXN7), undergo proteolytic processing that produces toxic fragments containing their polyQ domains. Investigating how ATXN2 is regulated by proteolysis is hindered by the lack of available molecular biological tools such as N-terminal ATXN2 antibodies to target and analyze the endogenous N-terminus of ATXN2. To circumvent this challenge, I developed a transient overexpression model of N-terminally tagged ATXN2 in HEK293E cells. Here, I demonstrate that both wild-type and mutant ATXN2 are targets of N-terminal proteolysis. I confirmed that ATXN2 produces an independent polyQ cleavage fragment like other polyQ proteins through basic molecular biology approaches such as Western blotting and immunoprecipitation. Additionally, I identified the specific region that is both necessary and sufficient for cleavage to occur via deletion mapping with multiple truncated ATXN2 mutants and reporter constructs. Further definition of ATXN2 as a target of proteolytic cleavage aligns it with other neurodegenerative polyQ proteins, and proteolysis is currently a less explored avenue of research for ATXN2-related disease development, progression, and therapeutic modalities. This work reveals a novel site that directs cleavage of ATXN2 and provides a potential avenue of investigation for how ATXN2 posttranslational modifications contribute to the progression of SCA2 and ALS.
    DOI
    10.13028/py2x-sn09
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51128
    Rights
    © 2022 Chitre.
    Distribution License
    All Rights Reserved
    ae974a485f413a2113503eed53cd6c53
    10.13028/py2x-sn09
    Scopus Count
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses
    Neurobiology Student Publications

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