Objective: Investigate the effects of diabetic features on the induction and severity of synucleinopathies such as Parkinson’s disease (PD).

Background: Type 2 diabetes (T2D) is a comorbidity associated with an increased risk and accelerated progression of PD. The hallmark features of T2D are hyperglycemia and insulin resistance, each with mechanisms predicted to contribute to PD. Hyperglycemia can lead to protein glycation, oxidative stress, and chronic inflammation. As insulin signaling via the PI3K/AKT pathway can be anti-apoptotic, insulin resistance could increase susceptibility to neurodegeneration of challenged neurons. In the present study, we leverage the use of the alpha-synuclein preformed fibril (a-syn PFF) model in combination with T1D and T2D rat models to examine the effects of hyperglycemia and insulin resistance on synucleinopathy severity.

Method: Two-month-old male Fischer 344 rats (n=130) received a high fat (45 kcal from fat) or control diet followed by intraperitoneal administration of the pancreatic beta cell toxin streptozotocin or vehicle. Rats were tested weekly to measure blood glucose and blood was collected monthly for biochemical assessments. After one month in a diabetic state (blood glucose ≥250 mg/dL), rats received bilateral intrastriatal injections of a-syn monomers or PFFs, and brains were collected 2 months later for histological and biochemical assessments.

Results: Blood collected will be used to measure the effect of the diabetic state on α-syn glycation. Histological assessments will evaluate the effects of diabetic features on a-syn containing inclusions and other potential pathology (tau) in the SN. Unbiased stereology will be used to assess loss of the dopaminergic phenotype and neurodegeneration in the SN. Biochemical assessments will be used to determine the effects of the diabetic state and synucleinopathy on the insulin signaling pathway and accumulation of glycated proteins.

Conclusion: Our previous data suggests impaired glucose metabolism and reduced expression of the insulin receptor expression are early features of synucleinopathy alone. Based on these findings, we expect the combination of diabetic features and synucleinopathy will accelerate and increase the magnitude of neurodegeneration. Additionally, we expect glycation of a-syn will impact aggregation, leading to more inclusion bearing neurons.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/assessment-of-the-impact-of-the-diabetic-features-hyperglycemia-and-insulin-resistance-on-fibril-induced-synucleinopathy/