Although, the poly(Q) disorders, namely, Huntington’s disease (HD), Spinal and bulbar muscular atrophy (SBMA or Kennedy’s disease), Spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 17), and Dentatorubral-pallidoluysian atrophy (DRPLA or Haw River syndrome) are caused by mutation in one gene and subsequent accumulation of resulted protein as neurotoxic aggregates or inclusion bodies (IBs); yet a plethora of cellular pathways are found to be involved in the pathogenesis and progression of the disease(s) (Tandon et al., 2024, Mier and Andrade-Navarro, 2021). Hence, development of effective therapeutics becomes challenging when several unrelated pathways are involved in the disease aetiology. Combinatorial therapeutic strategies, that target different aspects of the disease pathology, is emerging as a new tool (Arranz-Romera et al., 2019, Kabir et al., 2020). Therefore, targeting more than one compatible modifier gene/protein could be the answer to combat the multifaceted pathogenesis of poly(Q) disorders.
Several reports evidently suggest that InR mediated or insulin/insulin-like growth factor signalling (IIS) pathway can be utilized as a druggable target to achieve effective mitigation against poly(Q) toxicity (Pennuto et al., 2020, García-Huerta et al., 2020). Of note, targeted upregulation of InR has been demonstrated to alleviate several aspects of poly(Q) pathogenesis such as formation of inclusion bodies, autophagy, transcriptional dysregulation, and cell death (Raj and Sarkar, 2019). Insulin signalling, via IGF-1 has been reported to alleviate motor defects and cellular loss, reduce the expression of mutant ataxin-3 protein and enhance autophagy and mitochondrial function in SCA3 mice (Lin et al., 2022). Therefore, making it an ideal candidate for designing a combinatorial therapy. Our genetic screening identified dMyc as a compatible genetic modifier that delivers additive rescue against poly(Q) toxicity when used along with InR.
The Myc family of oncoproteins mainly function as transcription factors (Das et al., 2022), and are involved in the regulation of transcription, cell cycle, protein synthesis, cell adhesion, metabolism, etc. (Cole and Cowling, 2008, Venkateswaran and Conacci-Sorrell, 2020). Although, Myc is notoriously associated with cancers (Duffy et al., 2021, Dhanasekaran et al., 2022), it has been reported to be neuroprotective against poly(Q) toxicity (Singh et al., 2014, Raj and Sarkar, 2017). For the first time we report InR and Myc as combinatorial drug targets and their concurrent upregulation delivers substantial rescue against human ploy(Q) toxicity in Drosophila disease models.