Targeted Downregulation of dMyc Suppresses Pathogenesis of Human Neuronal Tauopathies in Drosophila by Limiting Heterochromatin Relaxation and Tau Hyperphosphorylation
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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.
KeywordsTauopathies Tau Phosphorylation Drosophila dMyc
We are thankful to Prof. Mel Feany (Harvard Medical School, USA) and the Bloomington Stock Center for providing different fly stocks used in this study. We gratefully thank Prof. Bob Eisenman (Fred Hutchinson Cancer Research Center, USA) for anti-dMyc and Prof. T. Lilja (Stockholm University, USA) for anti-CBP antibodies. This work was supported by research grants from the Department of Biotechnology (DBT), Government of India, New Delhi, India, to S.S. SIC is supported by the Senior Research Fellowship (SRF) from the University Grant Commission (UGC), New Delhi, India. We also thank Delhi University for financial support under R&D scheme, DST-FIST(L2) support to the Department, and Central Instrument Facility (CIF) at South Campus. We are grateful to Ms. Nabanita Sarkar and Ms. Nisha for technical support.
Three dimensional view of a normally developed mushroom body (MB) in adult brain of control Elav-Gal4/+ flies. (MP4 2518 kb)
Three dimensional view of a severely degenerated mushroom body (MB) and neuropil structures in tauWT expressing adult brain. (MP4 2658 kb)
Three dimensional view of a completely restored and normally developed mushroom body (MB) in tauWT expressing adult brain with reduced expression of dMyc. (MP4 2858 kb)
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