Human insulin modulates α-synuclein aggregation via DAF-2/DAF-16 signalling pathway by antagonising DAF-2 receptor in C. elegans model of Parkinson’s disease
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Rizwanul Haque1, Shamsuzzama1, Lalit Kumar1, Tanuj Sharma2, Soobiya Fatima1,3, Pooja Jadiya1, Mohammad I. Siddiqi2 and Aamir Nazir1
1 Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226 031, India
2 Laboratory of Computational Biology and Bioinformatics, Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226 031, India
3 Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi 110 001, India
Keywords: Parkinson’s; human insulin; aggregation; Daf-2; Caenorhabditis elegans (C. elegans)
Received: August 11, 2017 Accepted: September 29, 2017 Published: February 11, 2020
Insulin-signalling is an important pathway in multiple cellular functions and organismal ageing across the taxa. A strong association of insulin-signalling with Parkinson’s disease (PD) has been proposed but the exact nature of molecular events and genetic associations are yet to be understood. We employed transgenic C. elegans strain harboring human α-synuclein::YFP transgene, towards studying the aggregation pattern of α-synuclein, a PD-associated endpoint, under human insulin (Huminsulin®) treatment and DAF-16/DAF-2 knockdown conditions, independently and in combination. The aggregation was increased when DAF-16 was knocked-down independently or alongwith a co-treatment of Human insulin (HumINS) and decreased when DAF-2 was knocked-down independently or alongwith a co-treatment of HumINS; whereas HumINS treatment per se, reduced the aggregation. Our results depicted that HumINS decreases α-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 α-synuclein aggregation. Further by utilizing bioinformatics tools, we compared the differences between the binding sites of probable agonists and antagonists on DAF-2 including HumINS. Our results suggest that HumINS treatment and DAF-16 expression play a protective role against α-synuclein aggregation and its associated effects.
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