Objective: We have investigated whether the cellular prion protein interacts with alpha-synuclein in pancreatic cells of patients with synucleinopathies.

Background: Neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease are characterized by the progressive dysfunction and death of some nerve cells. Specific protein aggregates constitute the defining neuropathological characteristics of these diesases. One of the key events in the pathogenesis of neurodegenerative diseases is the ability of the amyloidogenic proteins to enter healthy cells and enhance the conversion of the endogenous protein into the aggregation-prone form. In Parkinson’s disease, α-synuclein fibrils deposit inside neurons and can be released and taken up by other cells. This fact could cause the spreading of the pathology and the neurodegeneration.

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 86 neurologically asymptomatic subjects. We studied the pancreatic tissue to assess the accumulation of PrP. Moreover, we performed proximity ligation assays to assess whether this protein interact in the pancreas of these subjects with the alpha-synuclein. We designed two specific PLA assays to detect the interaction between PrP and both the C and N terminal regions of the α-synuclein. Furthermore, we designed a specific PLA assay to detect the interaction between PrP and phosphorylated α-synuclein. Recently it has been shown that PrPC on the cell surface promotes the uptake of different fibrillar forms of α-synuclein through a direct binding by its N-terminal domain.

Results: We found a significant increase in cytoplasmic PRP expression in pancreatic β cells of subjects with synucleinopathies compared with neurologically asymptomatic subjects. Furthermore, we found a PrP/α-synuclein interaction in patients with phosphorylated α-synuclein pancreatic inclusions. This interaction also occurred between the PrP and the phosphorylated α-synuclein.

Conclusions: Our study shows for the first time, histological evidence of the interaction between PrPc and α-synuclein in pancreatic beta-cells of subjects with synucleinopathies. Although further research is needed, our results are in line with previous reports highlighting that the interaction between PrPc and α-synuclein, could lead to α-synuclein fibrils internalization. This process may have therapeutical applications, that will be further discussed.

References: De Cecco E, Legname G. The role of the prion protein in the internalization of α-synuclein amyloids. 2018. Prion. doi: 10.1080/19336896.2017.1423186.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/prp-as-a-receptor-of-alpha-synuclein-in-the-pancreas-of-patients-with-synucleinopathies/