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Peer-reviewedCC BY 4.0Frontiers in Neuroscience

Variably protease-sensitive prionopathy in the context of a complex proteinopathy: clinical and neuropathological challenges

  • Anika Simonovska Serra1,2
  • Claudia Marina Vargiu3
  • Sigrid Klotz2,4
  • Evelyn Berger-Sieczkowski2,4
  • Michaela Kreiter1,2
  • Marlene Leoni5
  • Alexandra Guttmann-Lattmanig6
  • Lukas Haider7,8,9
  • Guenther Regelsberger1,2
  • Piero Parchi3,10
  • Ellen Gelpi1,2
10 affiliations
  1. 1Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases (OERPE)
  2. 2Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna
  3. 3Istituto di Ricovero e Cura a Carattere Scientifico, Istituto delle Scienze Neurologiche di Bologna, University of Bologna
  4. 4Department of Neurology, Medical University of Vienna
  5. 5Diagnostic and Research Institute of Pathology, Medical University of Graz
  6. 6Department of Neurology, Medical University of Graz
  7. 7Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna
  8. 8Queen Square Institute of Neurology, University College London
  9. 9Department of Clinical Neuroscience, Karolinska Institutet
  10. 10Department of Biomedical and Neuromotor Sciences, University of Bologna
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Abstract

Variably protease-sensitive prionopathy (VPSPr) is the most recently identified sporadic human prion disease, displaying distinctive clinical and neuropathological features and a unique western blot profile. Clinically, it frequently presents with longer disease duration than classic sporadic Creutzfeldt-Jakob disease (sCJD), neuropathologically with characteristic prion protein (PrP) deposition patterns, and biochemically with variable resistance of PrP Sc to proteinase K (PK) digestion. Here, we describe clinico-pathological features of two new patients with VPSPr identified at postmortem examination, review current literature, and emphasize diagnostic challenges when combined with other neurodegenerative conditions. As in sCJD, the polymorphism M/V at codon 129 of the PRNP gene influences the phenotypic expression, which includes features within the frontotemporal lobar degeneration and motor neuron disease (FTLD-MND) spectrum. Genetic and molecular analysis, as well as postmortem neuropathological examination and western blotting (case 2) were performed. Case 1 with an MM genotype showed a prominent involvement of the motor cortex and striatum, consistent with the pyramidal and extrapyramidal clinical symptoms. The cerebellum was devoid of PrP deposits. Co-pathologies including tau pathology consistent with argyrophilic grain disease (AGD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) were detected as well. Case 2 with a VV genotype displayed a prominent involvement of the cerebellum with microplaques and a slightly different PrP staining pattern, compared to case 1. Both patients showed a prolonged disease duration, 7 years and 3.5 years, respectively. The clinical and neuropathological diagnosis of VPSPr remains challenging, especially in the presence of co-pathologies. The codon 129 M/V polymorphism modulates the clinic and/or pathological phenotypic expression of VPSPr within the FT(L)D-MND spectrum.

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Cite

BibTeXRIS
BibTeX
@article{serra2026variably,
  title = {{Variably protease-sensitive prionopathy in the context of a complex proteinopathy: clinical and neuropathological challenges}},
  author = {Anika Simonovska Serra and Claudia Marina Vargiu and Sigrid Klotz and Evelyn Berger-Sieczkowski and Michaela Kreiter and Marlene Leoni and Alexandra Guttmann-Lattmanig and Lukas Haider and Guenther Regelsberger and Piero Parchi and Ellen Gelpi},
  journal = {Frontiers in Neuroscience},
  year = {2026},
  month = oct,
  doi = {10.3389/fnins.2026.1950078},
  url = {https://www.frontiersin.org/articles/10.3389/fnins.2026.1950078/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Variably protease-sensitive prionopathy in the context of a complex proteinopathy: clinical and neuropathological challenges
AU  - Anika Simonovska Serra
AU  - Claudia Marina Vargiu
AU  - Sigrid Klotz
AU  - Evelyn Berger-Sieczkowski
AU  - Michaela Kreiter
AU  - Marlene Leoni
AU  - Alexandra Guttmann-Lattmanig
AU  - Lukas Haider
AU  - Guenther Regelsberger
AU  - Piero Parchi
AU  - Ellen Gelpi
PY  - 2026
DA  - 2026/10/14
JO  - Frontiers in Neuroscience
DO  - 10.3389/fnins.2026.1950078
UR  - https://www.frontiersin.org/articles/10.3389/fnins.2026.1950078/full
AB  - Variably protease-sensitive prionopathy (VPSPr) is the most recently identified sporadic human prion disease, displaying distinctive clinical and neuropathological features and a unique western blot profile. Clinically, it frequently presents with longer disease duration than classic sporadic Creutzfeldt-Jakob disease (sCJD), neuropathologically with characteristic prion protein (PrP) deposition patterns, and biochemically with variable resistance of PrP Sc to proteinase K (PK) digestion. Here, we describe clinico-pathological features of two new patients with VPSPr identified at postmortem examination, review current literature, and emphasize diagnostic challenges when combined with other neurodegenerative conditions. As in sCJD, the polymorphism M/V at codon 129 of the PRNP gene influences the phenotypic expression, which includes features within the frontotemporal lobar degeneration and motor neuron disease (FTLD-MND) spectrum. Genetic and molecular analysis, as well as postmortem neuropathological examination and western blotting (case 2) were performed. Case 1 with an MM genotype showed a prominent involvement of the motor cortex and striatum, consistent with the pyramidal and extrapyramidal clinical symptoms. The cerebellum was devoid of PrP deposits. Co-pathologies including tau pathology consistent with argyrophilic grain disease (AGD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) were detected as well. Case 2 with a VV genotype displayed a prominent involvement of the cerebellum with microplaques and a slightly different PrP staining pattern, compared to case 1. Both patients showed a prolonged disease duration, 7 years and 3.5 years, respectively. The clinical and neuropathological diagnosis of VPSPr remains challenging, especially in the presence of co-pathologies. The codon 129 M/V polymorphism modulates the clinic and/or pathological phenotypic expression of VPSPr within the FT(L)D-MND spectrum.
SN  - 1662-453X
SN  - 1662-4548
ER  -