MOLECULAR MECHANISMS AND PATHOGENIC CONSEQUENCES OF PRION PROTEIN (PRP) MISFOLDING IN CREUTZFELDT–JAKOB DISEASE: A SYSTEMATIC REVIEW

Jennica Joy A. Lopena¹; Mikaela Loraine N. Jermice¹; John David Candelaria¹; Gecelene C. Estorico¹⸴²

doi:10.5281/zenodo.21202672

Abstract

Creutzfeldt–Jakob disease (CJD) is a rare, rapidly progressive, and fatal neurodegenerative disorder characterized by the accumulation of misfolded prion proteins within the central nervous system. The conversion of the normal cellular prion protein (PrPᶜ) into the pathogenic isoform (PrPˢᶜ) represents the fundamental molecular event underlying disease initiation and progression. This systematic review aimed to synthesize peer-reviewed evidence published between 2015 and 2025 regarding the molecular mechanisms of prion protein misfolding and their contribution to the pathogenesis, propagation, and diagnosis of CJD. A systematic literature search was conducted in PubMed, Scopus, Web of Science, and ScienceDirect following PRISMA 2020 guidelines. Studies meeting predefined inclusion and exclusion criteria were screened, evaluated for methodological quality, and synthesized. A total of 34 studies were included in the final review. Evidence from the included studies indicates that CJD pathogenesis is driven by a complex network of molecular and cellular processes initiated by the structural conversion of α-helix-rich PrPᶜ into β-sheet-rich PrPˢᶜ, resulting in conformational instability, seeded protein aggregation, and prion propagation. Additional mechanisms identified include genetic susceptibility associated with PRNP mutations and codon 129 polymorphisms, proteostasis dysfunction, oxidative stress, mitochondrial impairment, neuroinflammation, synaptic dysfunction, and neuronal degeneration. Recent advances in cryogenic electron microscopy have provided high-resolution insights into strain-specific prion conformations and mechanisms of propagation, while diagnostic technologies such as realtime quaking-induced conversion (RT-QuIC), protein misfolding cyclic amplification (PMCA), cerebrospinal fluid biomarkers, and diffusion-weighted magnetic resonance imaging have substantially improved ante-mortem diagnostic accuracy. Collectively, the evidence highlights the multifactorial nature of CJD and underscores the importance of integrating molecular, genetic, and cellular perspectives to improve disease understanding, biomarker development, and future therapeutic strategies.

Keywords

Neurodegeneration, Protein aggregation, Proteostasis, Neuroinflammation, Oxidative stress, Amyloid genesis

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