Excess PrP<sup>C</sup> inhibits muscle cell differentiation via miRNA-enhanced liquid-liquid phase separation implicated in myopathy.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38065962.
- Also identified by DOI 10.1038/s41467-023-43826-7 and PMC identifier 10709375.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The cellular prion protein (PrP<sup>C</sup>) is required for skeletal muscle function. Here, we report that a higher level of PrP<sup>C</sup> accumulates in the cytoplasm of the skeletal muscle of six myopathy patients compared to controls. PrP<sup>C</sup> inhibits skeletal muscle cell autophagy, and blocks myoblast differentiation. PrP<sup>C</sup> selectively binds to a subset of miRNAs during myoblast differentiation, and the colocalization of PrP<sup>C</sup> and miR-214-3p was observed in the skeletal muscle of six myopathy patients with excessive PrP<sup>C</sup>. We demonstrate that PrP<sup>C</sup> 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 PrP<sup>C</sup>, 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.
Medical subject headings
- MicroRNAs
- Muscular Diseases
- PrPC Proteins