Drosophila Myc, a novel modifier suppresses the poly(Q) toxicity by modulating the level of CREB binding protein and histone acetylation

作者：Singh M Dhruba; Raj Kritika; Sarkar Surajit^*

来源：Neurobiology of Disease, 2014, 63: 48-61.

DOI：10.1016/j.nbd.2013.11.015

• Polyglutamine [poly(Q)] disorders
• Neurodegeneration
• Inclusion bodies
• Drosophila
• Myc
• CBP
• Histone acetylation

Polyglutamine or poly(Q) disorders are dominantly inherited neurodegenerative diseases characterised by progressive loss of neurons in cerebellum, basal ganglia and cortex in adult human brain. Overexpression of human form of mutant SCA3 protein with 78 poly(Q) repeats leads to the formation of inclusion bodies and increases the cellular toxicity in Drosophila eye. The present study was directed to identify a genetic modifier of poly(Q) diseases that could be utilised as a potential drug target. The initial screening process was influenced by the fact of lower prevalence of cancer among patients suffering with poly(Q) disorders which appears to be related to the intrinsic biological factors. We investigated if Drosophila Myc (a homologue of human cMyc proto-oncogene) harbours intrinsic property of suppressing cellular toxicity induced by an abnormally long stretch of poly(Q). We show for the first time that targeted overexpression of Drosophila Myc (dMyc) mitigates the poly(Q) toxicity in eye and nervous systems. Upregulation of dMyc results in a significant reduction in accumulation of inclusion bodies with residual poly(Q) aggregates localising into cytoplasm. We demonstrate that dMyc mediated suppression of poly(Q) toxicity is achieved by alleviating the cellular level of CBP and improved histone acetylation, resulting restoration of transcriptional machinery which are otherwise abbreviated due to poly(Q) disease conditions. Moreover, our study also provides a rational justification of the enigma of poly(Q) patients showing resistance to the predisposition of cancer.

• 出版日期2014-3