title: Targeted Downregulation of dMyc Suppresses Pathogenesis of Human Neuronal Tauopathies in Drosophila by Limiting Heterochromatin Relaxation and Tau Hyperphosphorylation.
abstract: Human tauopathies such as Alzheimer's Disease (AD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease etc., are a group of neurodegenerative diseases which are characterized by abnormal hyperphosphorylation of tau that leads to formation of neurofibrillary tangles. Recapitulating several features of human neurodegenerative disorders, the Drosophila tauopathy model displays compromised lifespan, locomotor function impairment, and brain vacuolization in adult brain which is progressive and age dependent. Here, we demonstrate that tissue-specific downregulation of the Drosophila homolog of human c-myc proto-oncogene (dMyc) suppresses tau-mediated morphological and functional deficits by reducing abnormal tau hyperphosphorylation and restoring the heterochromatin loss. Our studies show for the first time that the inherent chromatin remodeling ability of myc proto-oncogenes could be exploited to limit the pathogenesis of human neuronal tauopathies in the Drosophila disease model. Interestingly, recent reports on successful uses of some anti-cancer drugs against Alzheimer's and Parkinson's diseases in clinical trials and animal models strongly support our findings and proposed possibility.
authors.affiliation: Department of Genetics, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India.
authors.forename: Soram Idiyasan
authors.initials: SI
authors.lastname: Chanu
authors.affiliation: Department of Genetics, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India. sarkar@south.du.ac.in.
authors.forename: Surajit
authors.initials: S
authors.lastname: Sarkar
mesh_terms: D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D042002:Chromatin Assembly and Disassembly; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D005123:Eye / Q000378:metabolism / Q000648:ultrastructure; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006570:Heterochromatin; D006657:Histones; C000715470:MAS1 protein, human; C102284:Myc protein, Drosophila; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D016875:tau Proteins
keywords: Drosophila; Phosphorylation; Tau; Tauopathies; dMyc