The yeast prion protein Sup35 initiates α-synuclein pathology in mouse models of Parkinson’s disease

• Authors: Lanxia Meng, Wuhan University; Congcong Liu, Wuhan University; Yiming Li, Wuhan University; Guiqin Chen, Emory University; Min Xiong, Wuhan University; Ting Yu, Wuhan University; Lina Pan, Wuhan University; Xingyu Zhang, Wuhan University; Lingyan Zhou, Wuhan University; Tao Guo, Wuhan University; Xin Yuan, Wuhan University; Chaoyang Liu, Wuhan University; Zhaohui Zhang, Wuhan University; Zhentao Zhang, Wuhan University
• Journal Title: Science Advances
• Volume: Volume 9, Number 44
• Publisher: Science | 2023-11-01, Pages eadj1092-None
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1126/sciadv.adj1092
• Subjects: Biology, Neuroscience; Biology, Molecular; Health Sciences, Pathology
• Keywords: Parkinson’s disease; α-synuclein; Saccharomyces cerevisiae; Sup35; yeast prion protein

Abstract

Parkinson’s disease (PD) is characterized by the pathologic aggregation and prion-like propagation of α-synuclein (α-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with Saccharomyces cerevisiae (S. cerevisiae) in α-syn A53T transgenic mice accelerates the aggregation of α-syn. Furthermore, we found that Sup35, a prion protein from S. cerevisiae, is the key factor initiating α-syn pathology induced by S. cerevisiae. Sup35 interacts with α-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to α-syn pathology and PD-like motor impairment. The Sup35-seeded α-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates α-syn pathology in PD.