Unexpected decrease of full-length prion protein in macaques inoculated with prion-contaminated blood products.

Area of Science:

• Neuroscience
• Infectious Diseases
• Biochemistry

Background:

• Variant Creutzfeldt-Jakob disease (v-CJD) is a fatal human prion disease linked to bovine spongiform encephalopathy (BSE).
• Prion infectivity in blood poses a transfusion-related transmission risk.
• Previous studies showed experimental v-CJD in macaques, but most developed an atypical myelopathic syndrome.

Purpose of the Study:

• Investigate the pathology of the unexpected myelopathic syndrome in macaques exposed to v-CJD prions.
• Determine if abnormal prion protein (PrP^v-CJD) accumulation occurs in the central nervous system (CNS) of these animals.
• Explore the role of cellular prion protein (PrP) alterations in disease pathogenesis.

Main Methods:

• Experimental exposure of cynomolgus macaques to prion-contaminated blood products.
• Extensive analysis of the central nervous system (CNS) for abnormal prion protein (PrP^v-CJD) using conventional techniques.
• Detailed examination of cellular prion protein (PrP) patterns in the spinal cord.

Main Results:

• Most macaques developed a fatal myelopathic syndrome, not classical v-CJD.
• Abnormal prion protein (PrP^v-CJD) was undetectable in the CNS of myelopathic animals.
• Cellular PrP showed altered patterns, with a truncated C1 fragment predominant and loss of the N-terminal fragment.

Conclusions:

• The myelopathic syndrome suggests a broader spectrum of prion diseases beyond classical v-CJD.
• Loss of cellular prion protein (PrP) function, indicated by N-terminal fragment disappearance, may be linked to disease onset.
• This finding challenges the current understanding of prion disease pathogenesis, focusing on abnormal PrP conformations.