Objective: This study marks the inaugural attempt to investigate the direct effects of insulin on pathological α-synuclein accumulation induced by the addition of α-synuclein preformed fibrils in LUHMES cells, a human neuronal precursor-derived cell line capable of differentiation into mature dopaminergic neurons.

Background: Substantial evidence points towards an association between Parkinson’s disease (PD) and diabetes mellitus (DM). At the cellular level, prolonged elevation of glucose levels has been demonstrated to contribute to nigrostriatal degeneration in PD models. However, the direct influence of insulin signaling on abnormal α-synuclein accumulation – a hallmark of Parkinson’s disease – remains inadequately explored.

Method: Employing Western blot analysis, we scrutinized the expression of native α-synuclein and 10 μM αSyn preformed fibrils (PFFs) triggered α-synuclein in various media formulations, both with and without insulin. Additionally, cell death was quantified by measuring lactate dehydrogenase (LDH) released into the culture medium.

Results: Media lacking insulin exhibited a substantial reduction in α-synuclein accumulation, irrespective of whether triggered by native α-synuclein or PFFs. Intriguingly, the introduction of insulin at a relative volume demonstrated the potential to rescue this observed phenotype. Importantly, LDH levels did not exhibit significant differences between the groups with insulin and those without insulin.

Conclusion: This study pioneers the exploration of the direct impact of insulin on α-synuclein accumulation induced by preformed fibrils in LUHMES cells. The removal of insulin from the culture media significantly decreased α-synuclein levels without compromising cell viability, suggesting a potential link between insulin signaling and the pathology of Parkinson’s disease. In future investigations, we aim to delve deeper into the molecular mechanisms underlying the observed influence of insulin on α-synuclein accumulation in Parkinson’s disease. This will involve a meticulous examination of insulin receptor pathways and downstream signaling events. Additionally, our efforts will be directed towards the development of targeted therapeutic interventions aimed at modulating insulin signaling for the potential mitigation of α-synuclein pathology in Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unveiling-the-link-insulins-novel-role-in-modulating-%ce%b1-synuclein-accumulation-in-parkinsons-disease/