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Truncation of the TAR DNA-binding protein 43 is not a prerequisite for cytoplasmic relocalization, and is suppressed by caspase inhibition and by introduction of the A90V sequence variant
AstraZeneca, Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, United States.
AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, MA, United States of America / AstraZeneca, Discovery Science, Innovative Medicines and Early Development Biotech Unit, Mölndal, Sweden. (Bioinformatics)ORCID-id: 0000-0003-2899-3801
AstraZeneca, Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, United States / AstraZeneca, Neuroscience, Innovative Medicines and Early Development, Waltham, United States.
AstraZeneca, Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, United States / Department of Neuroscience, Tufts University, School of Medicine, Boston, MA, United States.
2017 (Engelska)Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 12, nr 5, artikel-id e0177181Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The RNA-binding and -processing protein TAR DNA-binding protein 43 (TDP-43) is heavily linked to the underlying causes and pathology of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In these diseases, TDP-43 is mislocalized, hyperphosphorylated, ubiquitinated, aggregated and cleaved. The importance of TDP-43 cleavage in the disease pathogenesis is still poorly understood. Here we detail the use of D-sorbitol as an exogenous stressor that causes TDP-43 cleavage in HeLa cells, resulting in a 35 kDa truncated product that accumulates in the cytoplasm within one hour of treatment. We confirm that the formation of this 35 kDa cleavage product is mediated by the activation of caspases. Inhibition of caspases blocks the cleavage of TDP-43, but does not prevent the accumulation of full-length protein in the cytoplasm. Using D-sorbitol as a stressor and caspase activator, we also demonstrate that the A90V variant of TDP-43, which lies adjacent to the caspase cleavage site within the nuclear localization sequence of TDP-43, confers partial resistance against caspase-mediated generation of the 35 kDa cleavage product.

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Public Library of Science , 2017. Vol. 12, nr 5, artikel-id e0177181
Nationell ämneskategori
Biokemi och molekylärbiologi
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URN: urn:nbn:se:his:diva-14040DOI: 10.1371/journal.pone.0177181ISI: 000401485500016PubMedID: 28510586Scopus ID: 2-s2.0-85019583583OAI: oai:DiVA.org:his-14040DiVA, id: diva2:1136076
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Tillgänglig från: 2017-08-25 Skapad: 2017-08-25 Senast uppdaterad: 2021-06-14Bibliografiskt granskad

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