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Impaired transmissibility of atypical prions from genetic CJDG114V
Ignazio Cali1, Fadi Mikhail1, Kefeng Qin1
1Department of Pathology (I.C., M.C.M., P.G.), Case Western University, Cleveland, OH; Department of Neurology (K.Q., F.M., C.G., A.S., L.Z., J.A.M.), University of Chicago; and Department of Biological Sciences (E.N.), DePaul University, Chicago, IL.
Objective:
To describe the clinicopathologic, molecular, and transmissible characteristics of genetic prion disease in a young man carrying the PRNP-G114V variant.
Methods:
We performed genetic, histologic, and molecular studies, combined with in vivo transmission studies and in vitro replication studies, to characterize this genetic prion disease.
Results:
A 24-year-old American man of Polish descent developed progressive dementia, aphasia, and ataxia, leading to his death 5 years later. Histologic features included widespread spongiform degeneration, gliosis, and infrequent PrP plaque-like deposits within the cerebellum and putamen, best classifying this as a Creutzfeldt-Jakob disease (CJD) subtype. Molecular typing of proteinase K-resistant PrP (resPrPSc) revealed a mixture of type 1 (∼21 kDa) and type 2 (∼19 kDa) conformations with only 2, rather than the usual 3, PrPSc glycoforms. Brain homogenates from the proband failed to transmit prion disease to transgenic Tg(HuPrP) mice that overexpress human PrP and are typically susceptible to sporadic and genetic forms of CJD. When subjected to protein misfolding cyclic amplification, the PrPSc type 2 (∼19 kDa) was selectively amplified.
Conclusions:
The features of genetic CJDG114V suggest that residue 114 within the highly conserved palindromic region (113-AGAAAAGA-120) plays an important role in prion conformation and propagation.
Insights
This study details a rare genetic prion disease (CJDG114V) in a young man. The G114V variant showed unique prion characteristics and failed to transmit to mice, suggesting altered propagation.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Genetic prion diseases are rare neurodegenerative disorders.
- The PRNP gene encodes the prion protein (PrP).
- Specific PRNP mutations can lead to familial Creutzfeldt-Jakob disease (CJD).
Purpose of the Study:
- To characterize the clinicopathologic, molecular, and transmissible features of a novel genetic prion disease caused by the PRNP-G114V variant.
- To understand the role of the G114V mutation in prion protein (PrP) conformation and disease propagation.
Main Methods:
- Genetic analysis of the PRNP gene.
- Histologic and molecular examination of brain tissue.
- In vivo transmission studies in transgenic mice.
- In vitro protein misfolding cyclic amplification (PMCA).
Main Results:
- A 24-year-old man with PRNP-G114V presented with progressive dementia, aphasia, and ataxia.
- Histopathology revealed spongiform degeneration and gliosis, consistent with a CJD subtype.
- The disease failed to transmit to Tg(HuPrP) mice, and PrPSc type 2 was selectively amplified.
- Unique PrPSc molecular signature with two glycoforms and specific molecular weight.
Conclusions:
- The PRNP-G114V variant causes a distinct form of genetic CJD.
- Residue 114 is crucial for prion conformation and propagation.
- The altered PrPSc characteristics may explain the lack of transmission in mouse models.
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