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Publications

Journal Article Epublish

PubMed: 42953028 DOI: 10.3389/fnins.2026.1950078

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

Front Neurosci 20:1950078

Authors: Anika Simonovska Serra, Claudia Marina Vargiu, Sigrid Klotz, Evelyn Berger-Sieczkowski, Michaela Kreiter, Marlene Leoni, Alexandra Guttmann-Lattmanig, Lukas Haider, Guenther Regelsberger, Piero Parchi, Ellen Gelpi

Affiliations

  • Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases (OERPE), Vienna, Austria. Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
  • Istituto di Ricovero e Cura a Carattere Scientifico, Istituto delle Scienze Neurologiche di Bologna, University of Bologna, Bologna, Italy.
  • Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
  • Department of Neurology, Medical University of Vienna, Vienna, Austria.
  • Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria. Department of Neurology, Medical University of Vienna, Vienna, Austria.
  • Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
  • Department of Neurology, Medical University of Graz, Graz, Austria.
  • Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria. Queen Square Institute of Neurology, University College London, London, United Kingdom. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases (OERPE), Vienna, Austria.
  • Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

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 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.

MeSH

Genes, Codon, Pathology, Prions, Signs And Symptoms, Cerebellum, Peptide Hydrolases, Genotype, Frontotemporal Lobar Degeneration, Prion Diseases