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Functions of the Atrophin-Brakeless protein complex in neurodegeneration and gene regulation
Prof Mattias Mannervik
Developmental Biology (Wenner-Gren Institute)
Swedish Research Council - Vetenskapsrådet (VR)
The aim of this research is to characterize the gene regulatory properties of Atrophin-1, the causative agent of the neurodegenerative disease dentatorubral-pallidoluysian atrophy, and its interaction partner Brakeless, with the goal of understanding and treating the gene expression changes that underlie this polyglutamine (polyQ) disorder. Many polyQ-expanded proteins are intimately linked to transcriptional control, including the transcriptional co-repressor Atrophin-1. It is thought that interaction of polyQ-expanded Atrophin-1 with its normal binding partners leads to neuronal toxicity. We have previously isolated a novel transcriptional co-repressor, Brakeless, required for Drosophila embryo development, and shown that it interacts with and functions together with Atrophin. To map the global function of Atrophin and Brakeless in gene regulation, we will perform genome-wide chromatin immunoprecipitation (ChIP) assays with Atrophin and Brakeless antibodies followed by massive parallel sequencing (ChIP-seq) from both Drosophila and human cells. This way, the genes that are directly regulated by Atrophin and Brakeless are identified, and relevant target genes of polyQ-expanded Atrophin-1 may be found. Characterization of further components in a 2 MDa Atrophin-Brakeless protein complex by mass spectrometry may lead to an understanding of the molecular mechanisms by which this complex represses transcription, and provide new candidate drug targets.
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