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dc.contributor.authorImler, Elliot
dc.contributor.authorPyon, Jin Sang
dc.contributor.authorKindelay, Selina
dc.contributor.authorTorvund, Meaghan
dc.contributor.authorZhang, Yong-Quan
dc.contributor.authorChandra, Sreeganga S
dc.contributor.authorZinsmaier, Konrad E
dc.date.accessioned2020-02-04T16:11:41Z
dc.date.available2020-02-04T16:11:41Z
dc.date.issued2019-10-30
dc.identifier.citationImler, E., Jin Sang Pyon, Kindelay, S., Torvund, M., Yong-quan Zhang, Chandra, S. S., & Zinsmaier, K. E. (2019, October 30). A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism. Retrieved January 27, 2020, from eLife website: https://elifesciences.org/articles/46607 ‌en_US
dc.identifier.issn2050-084X
dc.identifier.pmid31663851
dc.identifier.doi10.7554/eLife.46607
dc.identifier.urihttp://hdl.handle.net/10150/636888
dc.description.abstractThe autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.en_US
dc.description.sponsorshipNational Institute of Neurological Disorders and StrokeUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01NS083849, R21NS094809]en_US
dc.language.isoenen_US
dc.publisherELIFE SCIENCES PUBLICATIONS LTDen_US
dc.rightsCopyright © Imler et al. This article is distributed under the terms of the Creative Commons Attribution License.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectD. melanogasteren_US
dc.subjectcysteine-string proteinen_US
dc.subjectlysosomeen_US
dc.subjectneuronal ceroid lipofuscinosisen_US
dc.subjectneuroscienceen_US
dc.titleA Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanismen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Grad Interdisciplinary Program Neuroscien_US
dc.contributor.departmentUniv Arizona, Dept Neuroscien_US
dc.contributor.departmentUniv Arizona, Dept Mol & Cellular Biol, Undergrad Program Neurosci & Cognit Scien_US
dc.contributor.departmentUniv Arizona, Dept Mol & Cellular Biolen_US
dc.identifier.journalELIFEen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleeLife
refterms.dateFOA2020-02-04T16:11:42Z


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Copyright © Imler et al. This article is distributed under the terms of the Creative Commons Attribution License.
Except where otherwise noted, this item's license is described as Copyright © Imler et al. This article is distributed under the terms of the Creative Commons Attribution License.