Research Projects

The current century is witnessing a steep elevation in the global burden of age-associated diseases, mainly age-linked neurodegenerative diseases like Parkinson’s disease (PD). PD is characterised by various motor and non-motor symptoms that aggravate with age progression. Unfortunately, no currently available drug has shown promising efficacy in mitigating ageing or PD-linked pathologies. Moreover, new drug discovery costs billions of USD and is time-consuming. Drug repurposing offers a low-cost and less time-consuming option due to previously available toxicology, safety, and pharmacokinetics data. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterised by elevated blood glucose levels and pancreatic-cell dysfunction, resulting from decreased insulin production or insulin resistance. Recent literature and gene interaction studies show that T2DM, PD and ageing share common molecular targets and conserved pathways. Interestingly, metformin, the first-line drug for T2DM, has been recently reported to alleviate PD pathologies in T2DM patients and experimental PD models. through restoration of parkin, autophagy and AMPK activation in mice model. The convincing geroprotective effects of Metformin have led to its clinical trial studies: Targeting Ageing with Metformin (TAME). Owing to the promising results obtained from metformin, it is highly likely that other anti-diabetic drugs with antioxidant, insulin-regulating and mitochondria-targeting T2DM drug classes with promising pleiotropic effects could work as a lead target for anti-ageing and anti-PD drug remedy. These include DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 R agonists, and dual GIP-GLP-1 receptor agonists like FDA-listed T2DM drugs: Trelagliptin Succinate, Lobeglitazone Sulfate, Sitagliptin Fentanil Phosphate, and Imeglimin Hydrochloride. I perform dose optimisation of selected T2DM drugs in wild-type C. elegans. Then, geroprotective effects will be determined by lifespan analysis of the selected T2DM drugs. Then these drugs will be tested on the a-synuclein::YFP, lrrk-1::pDat-1::GFP,6-OHDA induced PD model of C. elegans model of PD on parameters like a-synuclein aggregation, lipid deposition, dopaminergic neuron degeneration and motor deregulation assays. Further, molecular and cellular markers of ageing and PD will be tested through ROS staining and oxidative stress reporter imaging, mitochondrial integrity reporters and autophagy detection post-drug treatment. Lastly, I will employ genetic mutants, RNAi, qPCR and western blot analysis to decipher the conserved signalling pathway (e.g., AMPK, mTOR) involved in anti-ageing and anti-PD effects of selected T2DM drugs in C. elegans. Overall, we hypothesise that T2DM drugs will be a promising target for curtailing ageing and PD-associated pathologies through the interconnected pathways of T2D, ageing and PD. This proposal will also aim to advance research in the field of other a-synucleinopathies and age-related disorders.