Mutant human torsinA, responsible for early-onset dystonia, dominantly suppresses GTPCH expression, dopamine levels and locomotion in Drosophila melanogaster

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dc.contributor.authorWakabayashi-Ito, Noriko
dc.contributor.authorAjjuri, Rami R.
dc.contributor.authorHenderson, Benjamin W.
dc.contributor.authorDoherty, Olugbenga M.
dc.contributor.authorBreakefield, Xandra O.
dc.contributor.authorO'Donnell, Janis M.
dc.contributor.authorIto, Naoto
dc.contributor.otherHarvard University
dc.contributor.otherMassachusetts General Hospital
dc.contributor.otherHarvard Medical School
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.date.accessioned2023-10-02T15:17:53Z
dc.date.available2023-10-02T15:17:53Z
dc.date.issued2015
dc.description.abstractDystonia represents the third most common movement disorder in humans with over 20 genetic loci identified. TOR1A (DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. Most cases of DYT1 dystonia are caused by a 3 bp (Delta GAG) deletion that results in the loss of a glutamic acid residue (Delta E302/303) in the carboxyl terminal region of torsinA. This torsinA Delta E mutant protein has been speculated to act in a dominant-negative manner to decrease activity of wild type torsinA. Drosophila melanogaster has a single torsin-related gene, dtorsin. Null mutants of dtorsin exhibited locomotion defects in third instar larvae. Levels of dopamine and GTP cyclohydrolase (GTPCH) proteins were severely reduced in dtorsin-null brains. Further, the locomotion defect was rescued by the expression of human torsinA or feeding with dopamine. Here, we demonstrate that human torsinA Delta E dominantly inhibited locomotion in larvae and adults when expressed in neurons using a pan-neuronal promoter Elav. Dopamine and tetrahydrobiopterin (BH4) levels were significantly reduced in larval brains and the expression level of GTPCH protein was severely impaired in adult and larval brains. When human torsinA and torsinA Delta E were co-expressed in neurons in dtorsin-null larvae and adults, the locomotion rates and the expression levels of GTPCH protein were severely reduced. These results support the hypothesis that torsinA Delta E inhibits wild type torsinA activity. Similarly, neuronal expression of a Drosophila Dtorsin Delta E equivalent mutation dominantly inhibited larval locomotion and GTPCH protein expression. These results indicate that both torsinA Delta E and DtorsinDE act in a dominant-negative manner. We also demonstrate that Dtorsin regulates GTPCH expression at the post-transcriptional level. This Drosophila model of DYT1 dystonia provides an important tool for studying the differences in the molecular function between the wild type and the mutant torsin proteins.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationWakabayashi-Ito, N., Ajjuri, R. R., Henderson, B. W., Doherty, O. M., Breakefield, X. O., O’Donnell, J. M., & Ito, N. (2015). Mutant human torsinA, responsible for early-onset dystonia, dominantly suppresses GTPCH expression, dopamine levels and locomotion inDrosophila melanogaster. In Biology Open (Vol. 4, Issue 5, pp. 585–595). The Company of Biologists. https://doi.org/10.1242/bio.201411080
dc.identifier.doi10.1242/bio.201411080
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12605
dc.languageEnglish
dc.language.isoen_US
dc.publisherCompany of Biologists
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectDystonia
dc.subjectDrosophila
dc.subjectGTP cyclohydrolase
dc.subjectTorsinA
dc.subjectMovement disorder
dc.subjectMESSENGER-RNA LOCALIZATION
dc.subjectTYROSINE-HYDROXYLASE
dc.subjectNUCLEAR-ENVELOPE
dc.subjectDYT1 DYSTONIA
dc.subjectPUNCH LOCUS
dc.subjectGENE-EXPRESSION
dc.subjectCELLS
dc.subjectSEQUENCES
dc.subjectBIOSYNTHESIS
dc.subjectINCLUSIONS
dc.subjectBiology
dc.titleMutant human torsinA, responsible for early-onset dystonia, dominantly suppresses GTPCH expression, dopamine levels and locomotion in Drosophila melanogasteren_US
dc.typeArticle
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