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dc.contributor.authorChitre, Monika
dc.contributor.authorEmery, Patrick
dc.date.accessioned2024-01-19T15:36:01Z
dc.date.available2024-01-19T15:36:01Z
dc.date.issued2023-12-21
dc.identifier.citationChitre M, Emery P. ATXN2 is a target of N-terminal proteolysis. PLoS One. 2023 Dec 21;18(12):e0296085. doi: 10.1371/journal.pone.0296085. PMID: 38128014; PMCID: PMC10735043.en_US
dc.identifier.eissn1932-6203
dc.identifier.doi10.1371/journal.pone.0296085en_US
dc.identifier.pmid38128014
dc.identifier.urihttp://hdl.handle.net/20.500.14038/52991
dc.description.abstractSpinocerebellar ataxia 2 (SCA2) is a neurodegenerative disorder caused by the expansion of the poly-glutamine (polyQ) tract of Ataxin-2 (ATXN2). Other polyQ-containing proteins such as ATXN7 and huntingtin are associated with the development of neurodegenerative diseases when their N-terminal polyQ domains are expanded. Furthermore, they undergo proteolytic processing events that produce N-terminal fragments that include the polyQ stretch, which are implicated in pathogenesis. Interestingly, N-terminal ATXN2 fragments were reported in a brain extract from a SCA2 patient, but it is currently unknown whether an expanded polyQ domain contributes to ATXN2 proteolytic susceptibility. Here, we used transient expression in HEK293 cells to determine whether ATXN2 is a target for specific N-terminal proteolysis. We found that ATXN2 proteins with either normal or expanded polyQ stretches undergo proteolytic cleavage releasing an N-terminal polyQ-containing fragment. We identified a short amino acid sequence downstream of the polyQ domain that is necessary for N-terminal cleavage of full-length ATXN2 and sufficient to induce proteolysis of a heterologous protein. However, this sequence is not required for cleavage of a short ATXN2 isoform produced from an alternative start codon located just upstream of the CAG repeats encoding the polyQ domain. Our study extends our understanding of ATXN2 posttranslational regulation by revealing that this protein can be the target of specific proteolytic cleavage events releasing polyQ-containing products that are modulated by the N-terminal domain of ATXN2. N-terminal ATXN2 proteolysis of expanded polyQ domains might contribute to SCA2 pathology, as observed in other neurodegenerative disorders caused by polyQ domain expansion.en_US
dc.language.isoenen_US
dc.relation.ispartofPLoS Oneen_US
dc.relation.urlhttps://doi.org/10.1371/journal.pone.0296085en_US
dc.rightsCopyright: © 2023 Chitre, Emery. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectTransfectionen_US
dc.subjectProteolysisen_US
dc.subjectImmunoblottingen_US
dc.subjectProtein sequencingen_US
dc.subjectImmunoprecipitationen_US
dc.subjectProtein domainsen_US
dc.subjectCell fusionen_US
dc.subjectAmino acid analysisen_US
dc.titleATXN2 is a target of N-terminal proteolysisen_US
dc.typeJournal Articleen_US
dc.source.journaltitlePloS one
dc.source.volume18
dc.source.issue12
dc.source.beginpagee0296085
dc.source.endpage
dc.source.countryUnited States
dc.identifier.journalPloS one
refterms.dateFOA2024-01-19T15:36:03Z
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeurobiologyen_US
dc.contributor.departmentEmery Lab
dc.contributor.studentMonika Chitre
dc.description.thesisprogramInterdisciplinary


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Copyright: © 2023 Chitre, Emery. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as Copyright: © 2023 Chitre, Emery. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.