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Dysregulation of core components of SCF complex in poly-glutamine disorders. [Drosophila facility]

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TitleDysregulation of core components of SCF complex in poly-glutamine disorders. [Drosophila facility]
Publication TypeJournal Article
Year of Publication2012
AuthorsBhutani S, Das A, Maheshwari M, Lakhotia SC, Jana NR
JournalCell Death Dis
Volume3
Paginatione428
Date Published2012 Nov 22
ISSN2041-4889
KeywordsAnimals, Cullin Proteins, Drosophila, Female, Humans, Huntington Disease, Machado-Joseph Disease, Male, Mice, Mice, Transgenic, Peptides, SKP Cullin F-Box Protein Ligases
Abstract

Poly-glutamine (polyQ) diseases are neurodegenerative disorders characterised by expanded CAG repeats in the causative genes whose proteins form inclusion bodies. Various E3 ubiquitin ligases are implicated in neurodegenerative disorders. We report that dysfunction of the SCF (Skp1-Cul1-F-box protein) complex, one of the most well-characterised ubiquitin ligases, is associated with pathology in polyQ diseases like Huntington's disease (HD) and Machado-Joseph disease (MJD). We found that Cullin1 (Cul1) and Skp1, core components of the SCF complex, are reduced in HD mice brain. A reduction in Cul1 levels was also observed in cellular HD model and fly models of both HD and MJD. We show that Cul1 is able to genetically modify mutant huntingtin aggregates because its silencing results in increased aggregate load in cultured cells. Moreover, we demonstrate that silencing dCul1 and dSkp1 in Drosophila results in increased aggregate load and enhanced polyQ-induced toxicity. Our results imply that reduced levels of SCF complex might contribute to polyQ disease pathology.

DOI10.1038/cddis.2012.166
Alternate JournalCell Death Dis
PubMed ID23171848
PubMed Central IDPMC3542602