Transactivation Domain of Human c-Myc Is Essential to Alleviate Poly(Q)-Mediated Neurotoxicity in Drosophila Disease Models.
Polyglutamine (poly(Q)) disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, represent a group of neurological disorders which arise due to an atypically expanded poly(Q) tract in the coding region of the affected gene. Pathogenesis of these disorders inside the cells begins with the assembly of these mutant proteins in the form of insoluble inclusion bodies (IBs), which progressively sequester several vital cellular transcription factors and other essential proteins, and finally leads to neuronal dysfunction and apoptosis. We have shown earlier that targeted upregulation of Drosophila myc (dmyc) dominantly suppresses the poly(Q) toxicity in Drosophila. The present study examines the ability of the human c-myc proto-oncogene and also identifies the specific c-Myc isoform which drives the mitigation of poly(Q)-mediated neurotoxicity, so that it could be further substantiated as a potential drug target. We report for the first time that similar to dmyc, tissue-specific induced expression of human c-myc also suppresses poly(Q)-mediated neurotoxicity by an analogous mechanism. Among the three isoforms of c-Myc, the rescue potential was maximally manifested by the full-length c-Myc2 protein, followed by c-Myc1, but not by c-MycS which lacks the transactivation domain. Our study suggests that strategies focussing on the transactivation domain of c-Myc could be a very useful approach to design novel drug molecules against poly(Q) disorders.
Department of Genetics, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India.
Kritika
K
Raj
Department of Genetics, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India. sarkar@south.du.ac.in.
Surajit
S
Sarkar
D000818:Animals; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000633:toxicity*; D000072417:Protein Domains; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C000715470:MAS1 protein, human; D010455:Peptides; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C097188:polyglutamine
Drosophila; Neurodegeneration; Poly(Q); c-myc