Genetic and Chemical Modifiers Of A CUG Toxicity Model in Drosophila
![Thumbnail](/xmlui/bitstream/handle/10234/12562/34013.pdf.jpg?sequence=7&isAllowed=y)
Visualitza/
Impacte
![Google Scholar](/xmlui/themes/Mirage2/images/uji/logo_google.png)
![Microsoft Academico](/xmlui/themes/Mirage2/images/uji/logo_microsoft.png)
Metadades
Mostra el registre complet de l'elementcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/8033
comunitat-uji-handle3:10234/8636
comunitat-uji-handle4:
INVESTIGACIONMetadades
Títol
Genetic and Chemical Modifiers Of A CUG Toxicity Model in DrosophilaAutoria
Data de publicació
2008Editor
Public Library of Science (PLoS)ISSN
1932-6203Tipus de document
info:eu-repo/semantics/articleVersió
info:eu-repo/semantics/acceptedVersionParaules clau / Matèries
Resum
Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to
myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed ... [+]
Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to
myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model
expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced
aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing
misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of
CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and further
supported by the co-localization of Muscleblind and CUG repeat RNA in ribonuclear foci. Targeted expression of CUG
repeats to the developing eye and brain mushroom bodies was toxic leading to rough eyes and semilethality, respectively.
These phenotypes were utilized to identify genetic and chemical modifiers of the CUG-induced toxicity. 15 genetic
modifiers of the rough eye phenotype were isolated. These genes identify putative cellular processes unknown to be altered
by CUG repeat RNA, and they include mRNA export factor Aly, apoptosis inhibitor Thread, chromatin remodelling factor
Nurf-38, and extracellular matrix structural component Viking. Ten chemical compounds suppressed the semilethal
phenotype. These compounds significantly improved viability of CUG expressing flies and included non-steroidal antiinflammatory
agents (ketoprofen), muscarinic, cholinergic and histamine receptor inhibitors (orphenadrine), and drugs that
can affect sodium and calcium metabolism such as clenbuterol and spironolactone. These findings provide new insights
into the DM1 phenotype, and suggest novel candidates for DM1 treatments [-]
Drets d'accés
http://rightsstatements.org/vocab/CNE/1.0/
info:eu-repo/semantics/openAccess
info:eu-repo/semantics/openAccess
Apareix a les col.leccions
- PSB_Articles [1322]
Els següents fitxers sobre la llicència estan associats a aquest element: