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dc.contributor.authorClemen, Christoph S
dc.contributor.authorTangavelou, Karthikeyan
dc.contributor.authorStrucksberg, Karl-Heinz
dc.contributor.authorJust, Steffen
dc.contributor.authorGaertner, Linda
dc.contributor.authorRegus-Leidig, Hanna
dc.contributor.authorStumpf, Maria
dc.contributor.authorReimann, Jens
dc.contributor.authorCoras, Roland
dc.contributor.authorMorgan, Reginald O
dc.contributor.authorFernandez, Maria-Pilar
dc.contributor.authorHofmann, Andreas
dc.contributor.authorMueller, Stefan
dc.contributor.authorSchoser, Benedikt
dc.contributor.authorHanisch, Franz-Georg
dc.contributor.authorRottbauer, Wolfgang
dc.contributor.authorBluemcke, Ingmar
dc.contributor.authorvon Hoersten, Stephan
dc.contributor.authorEichinger, Ludwig
dc.contributor.authorSchroeder, Rolf
dc.date.accessioned2017-05-03T15:19:48Z
dc.date.available2017-05-03T15:19:48Z
dc.date.issued2010
dc.date.modified2011-09-12T06:48:28Z
dc.identifier.issn0006-8950
dc.identifier.doi10.1093/brain/awq222
dc.identifier.urihttp://hdl.handle.net/10072/34902
dc.description.abstractMutations of the human valosin-containing protein gene cause autosomal-dominant inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. We identified strumpellin as a novel valosin-containing protein binding partner. Strumpellin mutations have been shown to cause hereditary spastic paraplegia. We demonstrate that strumpellin is a ubiquitously expressed protein present in cytosolic and endoplasmic reticulum cell fractions. Overexpression or ablation of wild-type strumpellin caused significantly reduced wound closure velocities in wound healing assays, whereas overexpression of the disease-causing strumpellin N471D mutant showed no functional effect. Strumpellin knockdown experiments in human neuroblastoma cells resulted in a dramatic reduction of axonal outgrowth. Knockdown studies in zebrafish revealed severe cardiac contractile dysfunction, tail curvature and impaired motility. The latter phenotype is due to a loss of central and peripheral motoneuron formation. These data imply a strumpellin loss-of-function pathogenesis in hereditary spastic paraplegia. In the human central nervous system strumpellin shows a presynaptic localization. We further identified strumpellin in pathological protein aggregates in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, various myofibrillar myopathies and in cortical neurons of a Huntington's disease mouse model. Beyond hereditary spastic paraplegia, our findings imply that mutant forms of strumpellin and valosin-containing protein may have a concerted pathogenic role in various protein aggregate diseases.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.format.extent2439355 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglish
dc.language.isoeng
dc.publisherOxford University Press
dc.publisher.placeUnited Kingdom
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom2920
dc.relation.ispartofpageto2941
dc.relation.ispartofissue10
dc.relation.ispartofjournalBrain
dc.relation.ispartofvolume133
dc.rights.retentionY
dc.subject.fieldofresearchStructural biology (incl. macromolecular modelling)
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchPsychology
dc.subject.fieldofresearchcode310112
dc.subject.fieldofresearchcode32
dc.subject.fieldofresearchcode52
dc.titleStrumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.rights.copyright© 2010 Oxford University Press. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Brain following peer review. The definitive publisher-authenticated version: Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases, Brain Brain (2010) 133 (10): 2920-2941 is available online at: http://dx.doi.org/10.1093/brain/awq222
gro.date.issued2010
gro.hasfulltextFull Text
gro.griffith.authorHofmann, Andreas


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