Polyglutamine or poly(Q) disorders such as Spinocerebellar ataxia(s) (SCAs), Huntington’s disease (HD), Spinal and Bulbar Muscular Atrophy (SBMA), Dentatorubral pallidoluysian syndrome (DRPLA) etc. represent a class of dominantly inherited neurodegenerative disorders which develop due to expansion of glutamine (Q) repeats in the coding region of target gene. The key factors for poly(Q) disease pathogenesis involve mis-folding of the mutated poly(Q) bearing protein and their subsequent accumulation in the cell in the form of inclusion bodies, which in turn leads to cellular toxicity and neurodegeneration. However, in spite of several pointers, the precise mechanism of poly(Q) disease pathogenesis and their suitable therapeutic approaches remains elusive. While finding a suitable drug target, we have demonstrated earlier that tissue specific upregulation of Drosophila myc (a homologue of human c-myc proto-oncogene) dominantly suppresses poly(Q) mediated cellular toxicity via histone acetylation and global transcriptional upregulation. Further, the rescue potential of human myc (c-myc) in alleviation of poly(Q) mediated neurotoxicity was examined utilizing multiple Drosophila transgenic lines expressing three different isoforms of transcripts encoded by human c-myc gene under the control of UAS promoter. Extensive genetic crosses, several immunostaining assays and appropriate microscopy techniques revealed that targeted over-expression of human myc (c-myc) also mitigates poly(Q)-induced cellular toxicity and neurodegeneration in SCA3 and HD models of Drosophila. Subsequent investigations suggest that transactivation domain of c-Myc protein which helps in restoring the poly(Q) induced cellular transcriptional impairments might be essential to achieve the rescue events.
We, therefore, propose that enhanced level of c-myc make a significant impact on the pathogenesis of human poly(Q) disorders and could be explored as a potential therapeutic target.