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[Prion induced spongiform encephalopathy of Creutzfeldt-Jakob disease]
1Departamento de Ciencias Neurológicas Oriente, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Abstract:
The infectious protein or prion (PrPSC) is a transmissible and replicable polypeptide, which arises from an abnormal folding of the PrP protein, by unknown mechanisms and without changes in the primary sequence of its amino acids. Its new spatial disposition arises from the substitution of its alpha helices by beta bands, which increase its structural stability, avoiding its complete proteolysis, resulting in a residual accumulation of prions. These prions induce the misfolding of normal PrP protein, generating their exponential increase, leading to a disturbance of neuronal homeostasis which results in the development of the fatal spongiform encephalopathy of the Creutzfeldt-Jakob disease (CJD). This is the most prevalent human prion disease, and 90% of cases are sporadic, suggesting the endogenous genesis of prions. There are different types of prions, identified based on the genetic variance of codon 129 amino acids of the prion protein. Meteonin (M) and Valine (V)), associated with the result of their enzymatic proteolysis, define prions type 1 (21 kDa) and type 2 (19 kDa). The Classical form of CJD produced by MM1 prion occurs in 70% of the cases. The Cerebellar form originated by the VV2 prion occurs in 15% of cases, the form with Kuru plates, associated with the prion MV2 occurs in 5%, and the Vacuolar, related to the MM2 prion occurs in 4%. CJD is always characterized by behavioral, motor, cognitive, and vision alterations and by findings in magnetic resonance imaging, electroencephalogram and cerebrospinal fluid that define each clinical and neuropathological form.
Insights
Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder caused by infectious prions. Prions misfold normal proteins, leading to exponential prion accumulation and neuronal damage, with specific prion types linked to distinct CJD subtypes.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Prions (PrPSc) are infectious, misfolded proteins causing fatal spongiform encephalopathies.
- Creutzfeldt-Jakob disease (CJD) is the most common human prion disease, often sporadic.
- Prion misfolding involves a shift from alpha-helices to beta-sheets, increasing stability and resistance to proteolysis.
Purpose of the Study:
- To elucidate the mechanisms of prion formation and their role in CJD pathogenesis.
- To classify CJD subtypes based on prion types and their associated clinical manifestations.
- To highlight diagnostic markers for CJD neuropathological forms.
Main Methods:
- Analysis of prion protein (PrP) misfolding and structural changes.
- Identification of prion types based on codon 129 polymorphism (Methionine/Valine) and proteolysis.
- Correlation of specific prion types (MM1, VV2, MV2, MM2) with distinct CJD clinical and neuropathological forms.
Main Results:
- Prion formation involves structural transition to beta-sheets, leading to accumulation and neuronal dysfunction.
- Four main CJD subtypes are identified: Classical (MM1, 70%), Cerebellar (VV2, 15%), Kuru-plaque (MV2, 5%), and Vacuolar (MM2, 4%).
- CJD presents with consistent behavioral, motor, cognitive, and visual symptoms, supported by neuroimaging and CSF findings.
Conclusions:
- Prion misfolding is central to CJD pathogenesis, with distinct prion types dictating disease subtypes.
- Understanding prion types and their genetic associations is crucial for diagnosing and potentially managing CJD.
- Sporadic CJD suggests endogenous prion genesis, warranting further investigation into its origins.
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