title: Drosophila Myc, a novel modifier suppresses the poly(Q) toxicity by modulating the level of CREB binding protein and histone acetylation.
abstract: Polyglutamine or poly(Q) disorders are dominantly inherited neurodegenerative diseases characterised by progressive loss of neurons in cerebellum, basal ganglia and cortex in adult human brain. Overexpression of human form of mutant SCA3 protein with 78 poly(Q) repeats leads to the formation of inclusion bodies and increases the cellular toxicity in Drosophila eye. The present study was directed to identify a genetic modifier of poly(Q) diseases that could be utilised as a potential drug target. The initial screening process was influenced by the fact of lower prevalence of cancer among patients suffering with poly(Q) disorders which appears to be related to the intrinsic biological factors. We investigated if Drosophila Myc (a homologue of human cMyc proto-oncogene) harbours intrinsic property of suppressing cellular toxicity induced by an abnormally long stretch of poly(Q). We show for the first time that targeted overexpression of Drosophila Myc (dMyc) mitigates the poly(Q) toxicity in eye and nervous systems. Upregulation of dMyc results in a significant reduction in accumulation of inclusion bodies with residual poly(Q) aggregates localising into cytoplasm. We demonstrate that dMyc mediated suppression of poly(Q) toxicity is achieved by alleviating the cellular level of CBP and improved histone acetylation, resulting restoration of transcriptional machinery which are otherwise abbreviated due to poly(Q) disease conditions. Moreover, our study also provides a rational justification of the enigma of poly(Q) patients showing resistance to the predisposition of cancer.
authors.affiliation: Department of Genetics, University of Delhi, South Campus, Benito Juarez Road, New Delhi 110 021, India.
authors.forename: M Dhruba
authors.initials: MD
authors.lastname: Singh
authors.affiliation: Department of Genetics, University of Delhi, South Campus, Benito Juarez Road, New Delhi 110 021, India.
authors.forename: Kritika
authors.initials: K
authors.lastname: Raj
authors.affiliation: Department of Genetics, University of Delhi, South Campus, Benito Juarez Road, New Delhi 110 021, India. Electronic address: sarkar@south.du.ac.in.
authors.forename: Surajit
authors.initials: S
authors.lastname: Sarkar
mesh_terms: D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3; D050882:CREB-Binding Protein / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D005123:Eye / Q000166:cytology / Q000648:ultrastructure; D005128:Eye Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D020258:Neurotoxicity Syndromes / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000633:toxicity*; D010786:Photoreceptor Cells / Q000648:ultrastructure; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D006657:Histones; C000715470:MAS1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C097188:polyglutamine; D050882:CREB-Binding Protein; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: CBP; Drosophila; Histone acetylation; Inclusion bodies; Myc; Neurodegeneration; Polyglutamine [poly(Q)] disorders