Genome-Wide Screens Identify Core Regulators of Cell Surface Prion Protein Expression

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Cellular prion protein (PrP^C) surface expression is crucial in prion disease pathogenesis.
• Understanding PrP^C regulation is vital for developing therapeutic strategies.

Purpose of the Study:

• To identify regulators of cell surface PrP^C expression in neuronal cells.
• To investigate cell-state-dependent regulation of PrP^C.

Main Methods:

• Genome-wide CRISPR/Cas9 knockout screens were performed in CAD5 cells (neuronal origin).
• Screens were conducted in both undifferentiated and differentiated CAD5 cell states.
• Validated regulators were identified through subsequent experiments.

Main Results:

• Identified 46 positive and 21 negative regulators in undifferentiated CAD5 cells.
• Identified 41 positive and 13 negative regulators in differentiated CAD5 cells.
• Found 23 core regulators shared across both cell states, enriched in GPI anchor biosynthesis pathways.

Conclusions:

• Cellular prion protein (PrP^C) regulation is influenced by cell state.
• Shared and unique regulators highlight distinct mechanisms in different neuronal states.
• Identified regulators provide targets for prion disease and neurodegenerative disease research.