Dysregulation of core components of SCF complex in poly-glutamine disorders
Open Access
- 22 November 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 3 (11), e428
- https://doi.org/10.1038/cddis.2012.166
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.Keywords
This publication has 45 references indexed in Scilit:
- A Sporadic Parkinson Disease Model via Silencing of the Ubiquitin-Proteasome/E3 Ligase Component SKP1APublished by Elsevier BV ,2009
- RNAi Screening in Drosophila Cells Identifies New Modifiers of Mutant Huntingtin AggregationPLOS ONE, 2009
- Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegansScience, 2009
- Expression cloning screening of a unique and full-length set of cDNA clones is an efficient method for identifying genes involved in Xenopus neurogenesisMechanisms of Development, 2005
- Co-chaperone CHIP Associates with Expanded Polyglutamine Protein and Promotes Their Degradation by ProteasomesJournal of Biological Chemistry, 2005
- The Ubiquitin–Proteasome Pathway is Necessary for Maintenance of the Postmitotic Status of NeuronsJournal of Molecular Neuroscience, 2005
- Accumulation of NEDD8 in neuronal and glial inclusions of neurodegenerative disordersNeuropathology and Applied Neurobiology, 2004
- The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-cateninOncogene, 1999
- Polyglutamine-Expanded Human Huntingtin Transgenes Induce Degeneration of Drosophila Photoreceptor NeuronsNeuron, 1998
- Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A.1998