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

The aggregation was increased when DAF-16 was knocked-down independently or along with a co-treatment of human insulin and decreased when DAF-2 was knocked-down independently or along with a co-treatment of Hum INS; whereas Hum INS treatment per se, reduced the aggregation.

The author's results depicted that Hum INS decreases -synuclein aggregation via DAF-2/DAF-16 pathway by acting as an antagonist for the DAF-2 receptor.

Dr. Aamir Nazir from the Division of Neuroscience and Ageing Biology at the CSIR-Central Drug Research Institute in Lucknow India reported in their Oncotarget Research Article that, "Neurodegenerative diseases (NDs) are age-associated ailments that pose a great challenge for the elderly population."

"Neurodegenerative diseases (NDs) are age-associated ailments that pose a great challenge for the elderly population."

- Dr. Aamir Nazir, Division of Neuroscience and Ageing Biology at the CSIR-Central Drug Research Institute

The insulin-signaling pathway is one of the most extensively studied and the progression of NDs has been proposed to be linked with this evolutionarily conserved pathway in various model systems.

The Nazir Research Team concluded in their Oncotarget paper that by employing C. elegans transgenic strain NL5901 which expresses human -syn in the body wall muscle we first, analyzed the -syn expression and aggregation after treatment of Hum INS. A potential linkage of Hum INS with -syn aggregation prompted us to study the effect of DAF-16/DAF-2 knockdown on -syn aggregation by employing reverse genetics approaches.

Worms in which DAF-16 was shut down, exhibited an increase in -syn aggregation and worms in which DAF-2 was shut down, exhibited a decrease in -syn aggregation.

Figure 1: Effect of HumINS on α-syn expression. (A–C) The expression of α-syn was assayed in NL5901 transgenic strain of C. elegans that expresses human α-syn::YFP transgene in their body wall muscles. The worms were treated with OP50 (control) (A), 10 U/ml HumINS (B), 15 U/ml HumINS (C). (D)There was a decrease in the α-syn level. Figure 1D is graphical representation for fluorescence intensity of α-syn::YFP as quantified using Image J software. ^***p < 0.001, Scale bar, 50 μm.

The data obtained are consistent with previous findings and also establishes the governance of -syn aggregation via Hum INS involves DAF-16 molecule, we carried out double treatment studies in which both DAF-16 was knocked-down along with Hum INS treatment.

The authors also observed a significant decrease in the -syn aggregation in the worms co-treated with DAF-16 RNAi and Hum INS and the effect was not synergistic with Hum INS treatment but aggregation was similar to the worms in which only DAF-16 was knocked-down.

IRS, a downstream signaling molecule in the insulin signaling pathway in mammals, modulates major molecular and biochemical responses through its signaling cascade, thus affecting apoptosis, oxidative conditions, growth, survival, energy metabolism, and cholinergic gene expression.

In C. elegans, the insulin-like signaling pathway is regulated by ILS ligands namely INS-1 to INS-39.

DAF-2 regulates functions similar to receptor kinases in the insulin-signaling pathway in humans.

This emergence of new concept i.e. modulation of the pathological hallmark of NDs by insulin-signaling pathways prompted us to study the relation of insulin and its related pathways in the context of PD.

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Full text - https://doi.org/10.18632/oncotarget.27366

Correspondence to - Aamir Nazir - anazir@cdri.res.in

Keywords - Parkinson's, human insulin, aggregation, Daf-2, Caenorhabditis elegans (C. elegans)

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