Abstract
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.
Highlights
Neurodegenerative diseases (NDs) are age associated ailments that pose a great challenge for the elderly population
Considering the importance of insulin pathway in NDs, we explored the effect of Human insulin (HumINS) on α-syn abundance/aggregation
A lot of evidence is accumulating through clinical and epidemiological research suggesting that drugs developed for the treatment of Type 2 Diabetes Mellitus (T2DM) might be highly beneficial for the treatment of Parkinson’s disease (PD) and associated diseases [27]
Summary
Neurodegenerative diseases (NDs) are age associated ailments that pose a great challenge for the elderly population. These diseases result from neuronal degeneration leading to altered neurotransmitter signalling and impaired neurobiological functions. Decreased insulin-signalling is reported to play protective role in neurodegenerative-associated proteotoxicity across species [5, 6]. IRS, a downstream signalling molecule in the insulin signalling pathway in mammals, modulates major molecular and biochemical responses through its signalling cascade, affecting apoptosis, oxidative conditions, growth, survival, energy metabolism, and cholinergic gene expression [9, 15]. It has been already reported that decreased insulin-signalling exerts a protective effect against neurodegenerative-associated proteotoxicity across species [5]
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