982C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
. Pragati; Surajit Sarkar

Affiliation: Department of Genetics, University of Delhi, South Campus, Dhaula Kuan, New Delhi, India

Keywords:
w. genetic modifiers of disease; f. Insulin signaling

Human neuronal tauopathies which include Alzheimer’s, Parkinson’s, Pick’s disease(s) etc. are group of neurodegenerative disorders characterised by aberrant tau hyperphosphorylation resulting in the formation of toxic tau oligomers, paired helical filaments (PHFs) and neurofibrillary tangles. These toxic aggregates were found in different specific regions of the brain resulting in various symptomatic features in patients. Even though several attempts are being made, the definite cause of these disorders remains unexplained certainly due to complex disease traits and limitations associated with the availability of human disease samples. We have reported earlier that targeted reduction of dmyc (a Drosophila homologue of cmyc proto-oncogene) constrains NFTs mediated tau pathogenesis. Further, in order to unravel the molecular insights, our findings suggest a pivotal role of shaggy (a Drosophila homologue of gsk3β, kinase) in conferring the dmyc mediated rescue against tauopathies. We observed that concurrent downregulation of both dmyc and shaggy confers an additive rescue in restricting tau hyperphosphorylation levels, neurofibrillary tangles formation, and in restoring heterochromatin loss to the physiological levels against tau-mediated toxicity in Drosophila. The subsequent analysis also showed that dmyc regulates shaggy activity via regulating protein phosphatase 2A (dPP2A) in a dose-dependent manner. Taken together, our study provides novel molecular insights about the role of shaggy in tau aetiology, which may aid in developing combinatorial drug(s) against the devastating human neuronal tauopathies.
Keywords: Drosophila; Tauopathies; dMyc; Shaggy; Neurofibrillary tangles