Nazir, Aamir, Jadiya, Pooja, Haque, Rizwanul, Kumar, Lalit, Shamsuzzama, Shamsuzzama, Fatima, Soobiya
[
International Worm Meeting,
2015]
Insulin signaling is an important pathway in multiple cellular functions and organismal aging across the taxa. Recent findings have linked defective insulin signaling to neurodegenerative Parkinson's disease (PD). In genetic model system Caenorhabditis elegans, insulin signaling is regulated by DAF-2, a tyrosine kinase receptor orthologous to the mammalian insulin/IGF receptor, which phosphorylates downstream transcription factor DAF-16 via AKT protein kinase activation. Despite crucial evidences on association of insulin signaling with PD, the exact nature of molecular events and genetic associations are yet to be understood. We employed transgenic C. elegans strain harboring human alpha-synuclein::YFP transgene, towards studying the aggregation pattern of alpha-synuclein, a PD associated endpoint, under 10 and 15 U/ml biphasic isophane insulin (Huminsulin®) treatment and DAF-16/DAF-2 knockdown conditions, independently and in combination. We observed that the aggregation was increased when DAF-16 was knocked down independently or alongwith a co-treatment of insulin and decreased when under DAF-2 was knocked down independently or alongwith a co-treatment of insulin; whereas Insulin treatment per se, reduced the aggregation and associated effects in a concentration dependent manner. Our results depicted that Human insulin decreases alpha-synuclein aggregation via DAF-2/DAF-16 pathway by acting as an antagonist for DAF-2 receptor. Knockdown of reported DAF-2 agonist (INS-6) and antagonists (INS-17 and INS-18) also resulted in a similar effect on alpha-synuclein aggregation. Further by utilizing bioinformatic tools, we compared the structural differences among agonists and antagonists including human insulin. Our results suggest that any deviation from the normal insulin signaling may greatly affect the alpha-synuclein aggregation pattern; further human insulin treatment and DAF-16 expression play a protective role against alpha-synuclein aggregation and its associated effects, thus providing interesting avenues for further research and possible therapeutic interventions.