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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
- Source :
- ACS Chemical Neuroscience. 12:3838-3854
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
Abstract
- 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.
- Subjects :
- Cell type
PrPSc Proteins
Prions
Physiology
animal diseases
Cognitive Neuroscience
Central nervous system
Hyperphosphorylation
Mitochondrion
Biochemistry
Prion Proteins
Prion Diseases
Mice
medicine
Animals
Humans
Chemistry
Brain
Colocalization
Cell Biology
General Medicine
nervous system diseases
Cell biology
HEK293 Cells
medicine.anatomical_structure
nervous system
Cytoplasm
Cell culture
alpha-Synuclein
Phosphorylation
Subjects
Details
- ISSN :
- 19487193
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Neuroscience
- Accession number :
- edsair.doi.dedup.....ffdc506d1a2ecd325fcefea50f1666ae