Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy

Jing Tao, Yanping Zeng, Bin Dai, Yin Liu, Xiaohan Pan, Li-Qiang Wang, Jie Chen, Yu Zhou, Zuneng Lu, Liwei Xie and Yi Liang ()
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Jing Tao: Wuhan University
Yanping Zeng: Renmin Hospital of Wuhan University
Bin Dai: Wuhan University
Yin Liu: Renmin Hospital of Wuhan University
Xiaohan Pan: State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences
Li-Qiang Wang: Wuhan University
Jie Chen: Wuhan University
Yu Zhou: Wuhan University
Zuneng Lu: Renmin Hospital of Wuhan University
Liwei Xie: State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences
Yi Liang: Wuhan University

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract The cellular prion protein (PrPC) is required for skeletal muscle function. Here, we report that a higher level of PrPC accumulates in the cytoplasm of the skeletal muscle of six myopathy patients compared to controls. PrPC inhibits skeletal muscle cell autophagy, and blocks myoblast differentiation. PrPC selectively binds to a subset of miRNAs during myoblast differentiation, and the colocalization of PrPC and miR-214-3p was observed in the skeletal muscle of six myopathy patients with excessive PrPC. We demonstrate that PrPC is overexpressed in skeletal muscle cells under pathological conditions, inhibits muscle cell differentiation by physically interacting with a subset of miRNAs, and selectively recruits these miRNAs into its phase-separated condensate in living myoblasts, which in turn enhances liquid–liquid phase separation of PrPC, promotes pathological aggregation of PrP, and results in the inhibition of autophagy-related protein 5-dependent autophagy and muscle bundle formation in myopathy patients characterized by incomplete muscle regeneration.

Date: 2023
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DOI: 10.1038/s41467-023-43826-7

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