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dc.contributor.authorZakirova, Zuchraen_US
dc.contributor.authorFanutza, Tomasen_US
dc.contributor.authorBonet, Justineen_US
dc.contributor.authorReadhead, Benen_US
dc.contributor.authorZhang, Weijiaen_US
dc.contributor.authorYi, Zhengzien_US
dc.contributor.authorBeauvais, Genevieveen_US
dc.contributor.authorZwaka, Thomas P.en_US
dc.contributor.authorOzelius, Laurie J.en_US
dc.contributor.authorBlitzer, Robert D.en_US
dc.contributor.authorGonzalez-Alegre, Pedroen_US
dc.contributor.authorEhrlich, Michelle E.en_US
dc.date.accessioned2018-03-20T15:58:54Z
dc.date.issued2018en_US
dc.identifier.citationZakirova, Z., T. Fanutza, J. Bonet, B. Readhead, W. Zhang, Z. Yi, G. Beauvais, et al. 2018. “Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions.” PLoS Genetics 14 (1): e1007169. doi:10.1371/journal.pgen.1007169. http://dx.doi.org/10.1371/journal.pgen.1007169.en
dc.identifier.issnen
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:35014396
dc.description.abstractDystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1 [THAP (Thanatos-associated protein) domain containing, apoptosis associated protein 1], a ubiquitously expressed transcription factor with DNA binding and protein-interaction domains, cause dystonia, DYT6. There is a unique, neuronal 50-kDa Thap1-like immunoreactive species, and Thap1 levels are auto-regulated on the mRNA level. However, THAP1 downstream targets in neurons, and the mechanism via which it causes dystonia are largely unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1 C54Y or ΔExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic LongTerm Depression, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays were consistent with those enrichments, and the plasticity defects were partially corrected by salubrinal. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence in the pathophysiology of several forms of inherited dystonia.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pgen.1007169en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798844/pdf/en
dash.licenseLAAen_US
dc.subjectBiology and Life Sciencesen
dc.subjectAnatomyen
dc.subjectBrainen
dc.subjectNeostriatumen
dc.subjectMedicine and Health Sciencesen
dc.subjectCerebral Cortexen
dc.subjectCerebellumen
dc.subjectNeurologyen
dc.subjectNeurodegenerative Diseasesen
dc.subjectMovement Disordersen
dc.subjectDystoniaen
dc.subjectExperimental Organism Systemsen
dc.subjectModel Organismsen
dc.subjectMouse Modelsen
dc.subjectAnimal Modelsen
dc.subjectCell Biologyen
dc.subjectCellular Typesen
dc.subjectAnimal Cellsen
dc.subjectNeuronsen
dc.subjectNeuroscienceen
dc.subjectCellular Neuroscienceen
dc.subjectSynaptic Plasticityen
dc.subjectDevelopmental Neuroscienceen
dc.subjectComputational Biologyen
dc.subjectGenome Analysisen
dc.subjectGene Ontologiesen
dc.subjectGeneticsen
dc.subjectGenomicsen
dc.subjectGene Expressionen
dc.titleMutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functionsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS Geneticsen
dash.depositing.authorOzelius, Laurie J.en_US
dc.date.available2018-03-20T15:58:54Z
dc.identifier.doi10.1371/journal.pgen.1007169*
dash.authorsorderedfalse
dash.contributor.affiliatedOzelius, Laurie


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