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dc.contributor.advisorPatrick Emeryen_US
dc.contributor.authorChitre, Monika
dc.date.accessioned2022-09-20T14:59:45Z
dc.date.available2022-09-20T14:59:45Z
dc.date.issued2022-08-08
dc.identifier.doi10.13028/py2x-sn09en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51128
dc.description.abstractAtaxin 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.en_US
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rights© 2022 Chitre.en_US
dc.rights.uriAll Rights Reserveden_US
dc.subjectneurodegenerationen_US
dc.subjectproteolysisen_US
dc.subjectataxin 2en_US
dc.titleInvestigating Proteolytic Processing of Ataxin 2, a Neurodegenerative Disease Associated Proteinen_US
dc.typeDoctoral Dissertationen_US
atmire.contributor.authoremailmonika.chitre@gmail.comen_US
dc.contributor.departmentNeurobiologyen_US
dc.contributor.departmentEmery Lab
dc.contributor.studentMonika Chitreen_US
dc.description.thesisprogramInterdisciplinaryen_US


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