Objective: We have investigated whether deposits of phosphorylated α-synuclein might be present in pancreatic tissue of subjects with synucleinopathies.

Background: Parkinson’s disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated α-synuclein in the peripheral nervous system. Although several lines of evidence suggest that a process analogous to peripheral insulin resistance also occurs in the brain of PD patients (even in the absence of diabetes), leading to a loss of insulin signaling and to the development of pathological features, the pancreas has received little attention in the context of PD. Moreover, a recent clinical trial using exenatide, a Glucagon-like peptide-1 agonist licensed for the treatment of T2DM, reported positive effects on off-medication motor scores in PD patients with no history of T2DM.

Methods: We studied pancreatic tissue from 39 subjects diagnosed with Parkinson’s disease, Lewy body Dementia or incidental Lewy bodies disease, as well as that from 34 neurologically asymptomatic subjects with diabetes mellitus and 52 control subjects. We examined the pancreatic accumulation of phosphorylated α-synuclein and of the islet amyloid polypeptide precursor (IAPP), an amyloidogenic protein that plays an unknown role in diabetes mellitus pathophysiology but that can promote α-synuclein oligomer formation in vitro. Moreover, we performed proximity ligation assays to assess whether these two proteins interact in the pancreas of these subjects.

Results: We found cytoplasmic phosphorylated α-synuclein deposits in pancreatic β cells of 14 subjects with Parkinson’s Disease (93%), in 11 subjects with Lewy Body Dementia (85%) and in 8 subjects with incidental Lewy bodies disease (73%). Furthermore, we found the same phosphorylated α-synuclein inclusions in 23 neurologically asymptomatic subjects with diabetes mellitus (68%) and in 9 control subjects (17%). In addition, we found an IAPP/α-synuclein interaction in patients with phosphorylated α-synuclein pancreatic inclusions.

Conclusions: The presence of phosphorylated α-synuclein inclusions in pancreatic β cells provides new evidence of an overlapping mechanism in the pathogenesis of diabetes mellitus, PD and DLB. Moreover, the interaction of IAPP and α-synuclein in the pancreatic β cells of patients may represent a novel target for the development of strategies to halt α-synuclein oligomers formation and treat these diseases.

References: Athauda D, Foltynie T. Insulin resistance and Parkinson’s disease: A new target for disease modification? Prog Neurobiol 2016; 145–146: 98–120. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 2017; 6736: 1–12.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/interaction-of-amyloidogenic-proteins-in-pancreatic-%ce%b2-cells-from-subjects-with-synuclenopathies/