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dc.contributor.authorNamikawa, Kazuhiko
dc.contributor.authorDorigo, Alessandro
dc.contributor.authorZagrebelsky, Marta
dc.contributor.authorRusso, Giulio
dc.contributor.authorKirmann, Toni
dc.contributor.authorFahr, Wieland
dc.contributor.authorDübel, Stefan
dc.contributor.authorKorte, Martin
dc.contributor.authorKöster, Reinhard W
dc.date.accessioned2019-06-03T14:22:03Z
dc.date.available2019-06-03T14:22:03Z
dc.date.issued2019-05-15
dc.identifier.citationJ Neurosci. 2019 May 15;39(20):3948-3969. doi: 10.1523/JNEUROSCI.1862-18.2019. Epub 2019 Mar 12.en_US
dc.identifier.issn1529-2401
dc.identifier.pmid30862666
dc.identifier.doi10.1523/JNEUROSCI.1862-18.2019
dc.identifier.urihttp://hdl.handle.net/10033/621794
dc.description.abstractPurkinje cells (PCs) are primarily affected in neurodegenerative spinocerebellar ataxias (SCAs). For generating animal models for SCAs, genetic regulatory elements specifically targeting PCs are required, thereby linking pathological molecular effects with impaired function and organismic behavior. Because cerebellar anatomy and function are evolutionary conserved, zebrafish represent an excellent model to study SCAs in vivo We have isolated a 258 bp cross-species PC-specific enhancer element that can be used in a bidirectional manner for bioimaging of transgene-expressing PCs in zebrafish (both sexes) with variable copy numbers for tuning expression strength. Emerging ectopic expression at high copy numbers can be further eliminated by repurposing microRNA-mediated posttranslational mRNA regulation.Subsequently, we generated a transgenic SCA type 13 (SCA13) model, using a zebrafish-variant mimicking a human pathological SCA13R420H mutation, resulting in cell-autonomous progressive PC degeneration linked to cerebellum-driven eye-movement deficits as observed in SCA patients. This underscores that investigating PC-specific cerebellar neuropathologies in zebrafish allows for interconnecting bioimaging of disease mechanisms with behavioral analysis suitable for therapeutic compound testing.SIGNIFICANCE STATEMENT SCA13 patients carrying a KCNC3R420H allele have been shown to display mid-onset progressive cerebellar atrophy, but genetic modeling of SCA13 by expressing this pathogenic mutant in different animal models has not resulted in neuronal degeneration so far; likely because the transgene was expressed in heterologous cell types. We developed a genetic system for tunable PC-specific coexpression of several transgenes to manipulate and simultaneously monitor cerebellar PCs. We modeled a SCA13 zebrafish accessible for bioimaging to investigate disease progression, revealing robust PC degeneration, resulting in impaired eye movement. Our transgenic zebrafish mimicking both neuropathological and behavioral changes manifested in SCA-affected patients will be suitable for investigating causes of cerebellar diseases in vivo from the molecular to the behavioral level.en_US
dc.language.isoenen_US
dc.publisherSociety of Neuroscienceen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectPurkinje cellsen_US
dc.subjectbioimagingen_US
dc.subjectcerebellumen_US
dc.subjectneuronal degenerationen_US
dc.subjectspinocerebellar ataxiaen_US
dc.subjectzebrafishen_US
dc.titleModeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalThe journal of neuroscienceen_US
dc.source.journaltitleThe Journal of neuroscience : the official journal of the Society for Neuroscience


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