Objective: The objective of this work is to study the interaction between α-synuclein and the insulin degrading enzyme in the pancreas of subjects with synucleinopathies.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). The cause of this neuronal death is still unclear, although the small alpha-synuclein (α-Syn) protein seems to play a pivotal role in PD pathophysiology. Several lines of evidence have suggested that the toxicity caused by α-Syn relies on its accumulation and oligomerization, which precedes the formation of large α-Syn aggregates (e.g., Lewy bodies) or fibrils. Recently, Sharma et al have proposed that the insulin degrading enzyme (IDE) appears to exert a key protective cellular role limiting intracellular levels of aggregate-prone, amyloidogenic peptides (such as IAPP, Aβ or interestingly α-Syn), by ensuring their degradation.

Methods: We studied pancreatic tissue from 39 subjects diagnosed with PD, Lewy body Dementia (DLB) or incidental Lewy bodies disease (ILBD), as well as that from 34 neurologically asymptomatic subjects with diabetes mellitus (T2DM) and 52 control subjects. We examined the pancreatic accumulation of IDE. Moreover, we designed two PLA assays to detect α-Syn oligomers and to assess if IDE and α-Syn were forming complexes within pancreatic β-cells.

Results: When IDE expression was examined, we failed to find differences between subjects with and without T2DM or between subjects diagnosed with a synucleinopathy and neurologically asymptomatic subjects. When we analyzed the PLA assays, we found that the interaction between IDE and α-Syn was decreased in both subjects diagnosed with a synucleinopathy or with T2DM antecedent. These results are in line with the hypothesis that IDE can neutralize amyloidogenic peptides forming complexes with proteins like α-Syn. Furthermore, the levels of pancreatic α-Syn were increased in both subjects with a synucleinopathy or with T2DM antecedent.

Conclusions: Our work provides, on the one hand, the first histological evidence that in pancreatic β-cells, IDE may exert a neuroprotective role neutralizing the formation of α-Syn oligomers. On the other hand, our work also provides histological evidence that this interaction between IDE and α-Syn is decreased in subjects with synucleinopathies, which leads to an increase of α-Syn oligomeric levels.

References: 1. Sharma SK, Chorell E, Wittung-Stafshede P (2015) Insulin-degrading enzyme is activated by the C-terminus of α-synuclein. Biochem Biophys Res Commun 466:192–195. doi: 10.1016/j.bbrc.2015.09.002.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/insulin-degrading-enzyme-a-novel-key-protein-against-alpha-synuclein-oligomers-formation/