Molecular Insights into Prion Degradation in Creutzfeldt Jakob Disease’s Challenges and Future Directions: A Review

Creutzfeldt-Jakob Disease (CJD) is a rare, fatal neurodegenerative disorder characterized by the accumulation of misfolded prion proteins (PrP^Sc) in the central nervous system. This review explores the molecular dynamics of prion misfolding and its implications for disease progression, with a particular focus on cellular degradation pathways. Key proteolytic systems, including the ubiquitin-proteasome system and the autophagy-lysosome pathway, are critically analyzed for their roles in the clearance of PrP^Sc. Special emphasis is placed on lysosomal involvement, where autophagosomes fuse to form autolysosomes, facilitating the breakdown of pathogenic proteins. The interplay between proteases and molecular chaperones in maintaining protein homeostasis is also discussed. Neuropathologically, CJD is marked by spongiform alterations, neuronal loss, and gliosis. Clinically, the disease presents with rapidly progressive dementia, motor impairments, and psychiatric symptoms. The heterogeneity of CJD is addressed by outlining its sporadic, familial, iatrogenic, and variant subtypes. Recent advances in diagnostic techniques, including real-time quaking-induced conversion (RT-QuIC) in peripheral tissues, as well as the integration of machine learning tools and AI-assisted biomarker discovery, are highlighted. Emerging therapeutic strategies targeting proteolytic and lysosomal pathways are also reviewed, offering potential for future intervention in this currently untreatable disease.