Cellular Prion Protein and its Peptides: Multifaceted Roles in Neurodegeneration and Emerging Biomarker Potential

Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by protein misfolding, synaptic dysfunction, and progressive neuronal loss. The cellular prion protein (PrPC), historically linked to prion diseases, is now recognized for its diverse roles in neuronal physiology and as a critical interaction hub for amyloidogenic proteins such as amyloid-β (Aβ), α‑synuclein, and tau. Understanding PrPC's complex processing and interactions is crucial for identifying novel therapeutic targets and diagnostic markers in these debilitating conditions.

This comprehensive review synthesizes current knowledge regarding PrPC's intricate structure-function relationships, its tightly regulated proteolytic processing (α-, β-, γ-cleavage, and ectodomain shedding), and its complex crosstalk with various disease-associated protein aggregates. The authors meticulously outline emerging translational opportunities, ranging from the development of PrP-derived peptide therapeutics to the utilization of fluid-based biomarkers capable of tracking disease onset and progression. The review integrates findings on PrPC as a ligand for low-density lipoprotein receptor-related protein-1 (LRP1) and the NMDA receptor (NMDAR), and its delivery via extracellular vesicles.

Cellular prion protein (PrPC) undergoes specific proteolytic processing, yielding soluble fragments and peptides with distinct biological activities. These PrP-derived peptides are shown to modulate crucial neurotrophic signaling pathways, enhance oxidative stress responses, and influence the uptake and toxicity of Alzheimer's disease-relevant soluble amyloid-β (Aβ), α‑synuclein, and tau aggregates. Recent research highlights PrPC's role as a ligand for LRP1 and NMDAR, demonstrating that shed PrPC and its derived peptides can initiate cell signaling and attenuate inflammatory responses, even when delivered via extracellular vesicles. > Ultrasensitive seed amplification assays (SAA), including RT-QuIC and PMCA, have revolutionized prion diagnostics and underscore the significant biomarker potential of both full-length PrPC and its proteolytic fragments for tracking neurodegenerative disease progression.