Objective: The aim of this work is to elucidate the role of amylin in both alpha-synuclein amyloid formation and Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) pathophysiology.

Background: Amylin is a small and highly amyloidogenic protein, whose aggregation has been implicated in the link between PD and type two diabetes mellitus (T2DM). Amylin has been related to PD pathophysiology since it interacts with alpha-synuclein promoting in vitro alpha-synuclein amyloid formation. We have provided histological evidence of this interaction in the pancreatic tissue of PD patients, and of the presence of amylin aggregates in PD brains.

Method: We evaluated post-mortem brain specimens from PD and DLB patients (n=50), and similar aged controls (n=35). We evaluated both amylin and SNCA mRNA expression levels by qPCR. Protein quantification by WB and ELISA were also performed. To assess  the “seeding” capacity of the amylin present in the brain, we optimized the RT-QuIC assay. For the amylin/alpha-synuclein interaction assessment two complementary techniques were used. Then, we generated in vitro human amylin oligomers, and characterized them by electronic microscopy and evaluated their seeding capacity. Once stablished, we characterized oligomer cytotoxicity in human dopaminergic neurons, and then performed an RNA-seq study to unravel the molecular pathways implicated in neuronal death.

Results: The main findings of our work are that we found amylin deposition in the brain of 85% of subjects with Parkinson’s disease examined.  Furthermore, we found that the brain of PD and DLB patients have amyloidogenic amylin and this amyloidogenic amylin causes, at very low concentrations, dopaminergic neuronal death in cell culture. The mechanism of this cellular death will be further discussed.

Conclusion: We show for the first time that amylin oligomers are able to cause dopaminergic neuronal death. Furthermore, taking advantage of the new molecular techniques available, we provided a molecular explanation of the mechanism which induce this cell death. On the other hand, we also demonstrate that amylin is able to misfold alpha-synuclein and that this interaction is happening in the brain of PD and DLB patients, thus this may represent a novel target to develop therapies for this disease.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/unraveling-the-role-of-amylin-oligomers-in-synucleinopathies/