American Chemical Society
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Accumulation of Prion and Abnormal Prion Protein Induces Hyperphosphorylation of α‑Synuclein in the Brain Tissues from Prion Diseases and in the Cultured Cells

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journal contribution
posted on 2021-10-01, 09:14 authored by Dong-Dong Chen, Li-Ping Gao, Yue-Zhang Wu, Jia Chen, Chao Hu, Kang Xiao, Cao Chen, Qi Shi, Xiao-Ping Dong
Prion disease (PrD) and Parkinson’s disease (PD) are neurodegenerative diseases characterized by aggregation of misfolded proteins in brain tissues, including protease-resistant prion protein (PrPSc) in PrD and α-synuclein in PD. In recent years, overlap of these two proteins has attracted increased attention, and cross-seeding of prion proteins by aggregated α-synuclein has been proposed. However, the changes in α-synuclein after prion infection are still unclear. In this study, we showed that α-synuclein expression was significantly decreased in the brains of prion-infected rodent models, in the SMB-S15 cell line, which exhibits persistent prion replication, and in the brains of humans with PrDs. Meanwhile, α-synuclein phosphorylated at serine 129­(p­(S129)-α-synuclein) was significantly increased in the brains of scrapie-infected mice and prion-infected SMB-S15 cells. The increased p­(S129)-α-synuclein colocalized with GFAP- and NeuN-positive cells in the brains of scrapie-infected mice. p­(S129)-α-synuclein was also observed in the cytoplasm of SMB-S15 and HEK-293 cells transiently expressing an abnormal form of prion protein (Cyto-PrP). Molecular interactions between PrP and α-synuclein were detected in recombinant proteins, normal and prion-infected brain tissues, and cultured cells. The increased p­(S129)-α-synuclein colocalized with PrP signals from prion-infected SMB-S15 and HEK-293 cells expressing Cyto-PrP. Moreover, increased morphological colocalization of p­(S129)-α-synuclein with mitochondrial markers was also detected in the two cell types. Our results indicate that prion replication and accumulation in cells and brains induce hyperphosphorylation of α-synuclein, particularly at S129, which may aggravate mitochondrial damage and facilitate α-synuclein aggregation in the central nervous system tissues from PrDs.