A Systems-Level Theoretical Framework for Prion Disease Resolution Through Coordinated Suppression, Clearance, Disaggregation, and Functional Protein Replacement

Prion diseases are fatal neurodegenerative disorders characterized by the misfolding of prion proteins into self-propagating aggregates that drive rapid neuronal dysfunction and death. Despite advances in understanding prion biology, existing approaches largely target isolated aspects of disease progression—such as reducing prion protein expression or inhibiting aggregation—without addressing the full pathological system. As a result, residual prion proteins and aggregates remain sufficient to sustain disease progression. In this study, we propose a unified theoretical framework that integrates multiple complementary strategies to address prion disease at the systems level. The model combines suppression of prion protein synthesis, immune-mediated clearance of residual prion proteins, disaggregation of existing prion aggregates, inhibition of further aggregation, and functional replacement of prion protein activity through homologous protein variants. By conceptually coordinating these mechanisms, the framework aims to eliminate both the source and persistence of pathogenic prion species while preserving essential cellular functions. We further discuss the broader implications of this approach for other neurodegenerative disorders associated with protein misfolding and aggregation, suggesting that prion disease may serve as a paradigmatic model for reversible aggregation-driven pathology. Ethical, immunological, and regulatory challenges—particularly those related to immune modulation and proteostasis imbalance—are acknowledged as critical considerations for future investigation. This work provides a theoretical foundation for integrated strategies targeting protein aggregation diseases and highlights key directions for subsequent experimental validation.