Objective: Here we sought to investigate mechanisms by which insulin resistance affects PD pathogenesis in-vitro, and whether restoration of insulin signaling, using GLP-1 agonist exenatide is a valid therapeutic target in PD.

Background: Type 2 diabetes is a recognized risk factor for the development of PD, and accelerates disease progression in PD, though the nature of the molecular interaction remains uncertain. The development of neuronal insulin resistance (IR) is now thought to play an important role in neurodegeneration, and pharmacological approaches to restore insulin signaling  using GLP-1 agonists such as exenatide appear promising.

Method: We utilized a human iPSC platform to generate midbrain dopaminergic (mDA) neurons from healthy controls and patients with A53T mutations and used live-cell imaging and electrochemiluminescence assays to quantify cellular phenotypes. We used two approaches to model PD: a model based on the A53T mutations, akin to familial PD, and a model based on applying external toxic ‘oligomers’ of alpha-synuclein to control neurons, akin to idiopathic PD. Neurons were also treated with exenatide to ascertain any neuroprotective effects.

Results: A53T dopaminergic neurons exhibit insulin resistance. After starving neurons of insulin overnight, A53T neurons demonstrated significantly reduced p-Akt expression to ever increasing concentrations of insulin treatment, compared to normal physiological responses seen in control neurons. A53T neurons demonstrate increased protein aggregate formation, mitochondrial dysfunction, oxidative stress, altered lysosomal pathology, and cell death compared to control neurons. These effects were associated with elevated markers of insulin resistance (IRS-1p312) and reduced expression of downstream pAkt (Ser473). These effects were completely attenuated by treatment with exenatide (25nM) for 10 days. In a model of idiopathic PD, pretreatment of neurons with exenatide protected neurons from oligomer-induced cellular stress and death.

Conclusion: Neuronal insulin resistance may be a critical shared feature uniting metabolism and neurodegeneration, and represents a valid target for neuroprotection. In addition to preventing cell death, exenatide reverses neuronal insulin resistance, and is able to improve cellular health through a range of pathways, including organelle homeostasis, and reducing protein aggregation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exenatide-protects-ipsc-derived-dopaminergic-neurons-with-a53t-mutation-through-restoration-of-insulin-signaling/