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Transactivation Domain of Human c-Myc Is Essential to Alleviate Poly(Q)-Mediated Neurotoxicity in Drosophila Disease Models

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Abstract

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.

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Acknowledgements

We are thankful to Prof. J. Troy Littleton (MIT, USA) and Prof. Benassayag (Université Paul Sabatier, Toulouse, France) for providing some fly stocks utilised in this study. We also thank Bloomington Stock Center, Indiana, USA, for fly stocks. This work was supported by a research grant (Ref. no. BT/PR4937/MED/30/727/2012) from the Department of Biotechnology (DBT), Government of India, New Delhi, to S.S. KR is supported by the Senior Research Fellowship (SRF) from University Grant Commission (UGC), New Delhi. We also thank Delhi University for the financial support under R&D and DU/DST-PURSE schemes. The financial support to the department under DSTFIST(L2) is thankfully acknowledged. We are grateful to Ms. Nabanita Sarkar and Ms. Soram Idiyasan Chanu for the technical help.

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  1. Department of Genetics, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, 110 021, India

    Kritika Raj & Surajit Sarkar

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  1. Kritika Raj
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  2. Surajit Sarkar
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Correspondence to Surajit Sarkar.

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Raj, K., Sarkar, S. Transactivation Domain of Human c-Myc Is Essential to Alleviate Poly(Q)-Mediated Neurotoxicity in Drosophila Disease Models. J Mol Neurosci 62, 55–66 (2017). https://doi.org/10.1007/s12031-017-0910-4

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  • DOI: https://doi.org/10.1007/s12031-017-0910-4

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