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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.

Human polyglutamine [poly(Q)] disorders such as Huntington's disease, different types of ataxias, etc. are devastating brain illnesses which are characterised by the presence of neurotoxic protein aggregates in the affected neurons. We have recently reported that S6K/4E-BP mediated growth promoting branch of insulin signalling pathway alleviates human poly(Q) induced neurotoxicity in Drosophila disease models. Since, the S6K/4E-BP sub-pathway can be stimulated by various amino acids; we extended our investigation to examine if oral feeding of amino acids delivers rescue against human poly(Q) toxicity in Drosophila. We utilised Drosophila models of two different poly(Q) disorders to test our hypothesis. Glutamine was fed to the test flies orally mixed in the food. Control and treated flies were then tested for different parameters, such as formation of poly(Q) aggregates and neurodegeneration, to evaluate glutamine's proficiency in mitigating poly(Q) neurotoxicity. Our study, for the first time, reports that glutamine feeding stimulates the growth promoting S6K/4E-BP branch of insulin signalling pathway and restricts pathogenesis of poly(Q) disorders in Drosophila disease models. We noted that glutamine treatment restricts the formation of neurotoxic poly(Q) aggregates and minimises neuronal deaths. Further, glutamine treatment re-establishes the chromatin architecture by improving the histone acetylation which is otherwise compromised in poly(Q) expressing neuronal cells. Since, the insulin signalling pathway as well as mechanism of action of glutamine are fairly conserved between human and Drosophila, our finding strongly suggests that glutamine holds immense potential to be developed as an intervention therapy against the incurable human poly(Q) disorders. [ABSTRACT FROM AUTHOR]

Increasing reports suggest insulin signalling pathway as a putative drug target against polyglutamine [poly(Q)] disorders, such as Huntington's disease (HD), Spinocerebellar ataxias (SCA) 1, 2, 3 etc. However, studies on drug-based stimulation of insulin signalling cascade to mitigate poly(Q) pathogenesis are lacking. In our study, we adopted an evidence-based approach to examine if some established insulin stimulating drug can be utilized to restrict poly(Q) aetiology in Drosophila disease models. For the first time, we report that glipizide, an FDA approved anti-diabetic drug upregulates insulin signalling in poly(Q) expressing tissues and restricts formation of inclusion bodies and neurodegeneration. Moreover, it reinstates the chromatin architecture by improving histone acetylation, which is otherwise abrogated due to poly(Q) toxicity. In view of the functional conservation of insulin signalling pathway in Drosophila and humans, our finding strongly suggests that glipizide can be repurposed as an effective treatment strategy against the neurodegenerative poly(Q) disorders. Also, with appropriate validation studies in mammalian disease models, glipizide could be subsequently considered for the clinical trials in human patients. • Glipizide upregulates insulin signalling in human poly(Q) expressing tissues in Drosophila. • Glipizide restricts formation of poly(Q) aggregates and neurodegeneration. • Glipizide improves histone acetylation and reinstate chromatin architecture in poly(Q) expressing cells. • Glipizide may be repurposed to restrict pathogenesis of human poly(Q) disorders. [ABSTRACT FROM AUTHOR]

Human neurodegenerative polyglutamine [poly(Q)] disorders, such as Huntington's disease (HD) and spinocerebellar ataxias (SCA), are characterised by an abnormal expansion of CAG repeats in the affected gene. The mutated proteins misfold and aggregate to form inclusion bodies that sequester important factors involved in cellular transcription, growth, stress and autophagic response and other essential functions. The insulin signalling pathway has been demonstrated as a major modifier and a potential drug target to ameliorate the poly(Q) mediated neurotoxicity in various model systems. Insulin signalling cascade harbours several downstream sub-pathways, which are synergistically involved in discharging indispensable biological functions such as growth and proliferation, metabolism, autophagy, regulation of cell death pathways etc. Hence, it is difficult to conclude whether the mitigation of poly(Q) neurotoxicity is an accumulative outcome of the insulin cascade, or the result of a specific sub-pathway. For the first time, we report that the ligand binding domain of insulin receptor mediated downstream growth promoting sub-pathway plays the pivotal role in operating the rescue event. We show that the growth promoting activity of insulin cascade is essential to minimize the abundance of inclusion bodies, to restrict neurodegeneration, and to restore the cellular transcriptional balance. Subsequently, we noted the involvement of the mTOR/S6k/4E-BP candidates in mitigating poly(Q) mediated neurotoxicity. Due to the conserved cellular functioning of the insulin cascade across species, and availability of several growth promoting molecules, our results in Drosophila poly(Q) models indicate towards a possibility of designing novel therapeutic strategies to restrict the pathogenesis of devastating human poly(Q) disorders. [Display omitted] • Ligand binding domain of insulin receptor mediates downstream growth promoting branch of insulin signalling in Drosophila. • Growth promoting sub-pathway of insulin signalling is essential to confer rescue against poly(Q) disorders. • Growth promotion is mediated by S6k/4E-BP to restore chromatin architecture and transcriptional balance. • Our study may potentially aid in designing of a novel therapeutic strategy against poly(Q) disorders. [ABSTRACT FROM AUTHOR]