Rare Prion Disease VPSPr Hides Among Other Proteinopathies, Two New Cases Reveal

A rare and elusive human prion disease called variably protease-sensitive prionopathy (VPSPr) is once again proving difficult to pin down. In a new study published in Frontiers in Neuroscience, researchers at the Medical University of Vienna and collaborating institutions describe two Austrian patients whose disease was only definitively identified at postmortem examination, underscoring how easily this condition can hide beneath other neurodegenerative disorders and mimic frontotemporal dementia or motor neuron disease during life.

VPSPr was first described in 2008 as a distinct entity among sporadic prion diseases, and fewer than 150 cases have been reported worldwide since then. Like all prion diseases, it is driven by the conversion of the normal, alpha-helix-rich cellular prion protein into a pathologic, beta-sheet-rich conformer known as PrP-Sc, which becomes insoluble and aggregates in the central nervous system. But VPSPr behaves differently from classic sporadic Creutzfeldt-Jakob disease (sCJD) in a crucial biochemical respect: the resistance of its abnormal prion protein to digestion by proteinase K is variable and significantly lower than in sCJD, producing a unique western blot profile. Its seeding activity is also reduced, which likely explains why the RT-QuIC assay in cerebrospinal fluid is negative in most cases.

That biochemical peculiarity has cascading diagnostic consequences. Neuroimaging with cranial MRI and FDG-PET is often inconclusive because the typical cortical or basal ganglia hyperintensities seen in classic prion disease are frequently absent. The 14-3-3 protein in cerebrospinal fluid, a common surrogate marker, often remains negative as well. Clinically, the disease course is considerably longer than sCJD, often lasting several years, and symptoms span extrapyramidal, psychiatric, cognitive, pyramidal and cerebellar domains. Which of these dominates depends strongly on the polymorphism at codon 129 of the PRNP gene, the same genetic modifier that shapes phenotypes in sCJD.

The research team, led by Anika Simonovska Serra and Ellen Gelpi, reviewed the published literature and found a consistent pattern. Methionine/methionine (MM) carriers, who average around 69 years at onset, more frequently present with extrapyramidal and cerebellar symptoms, and during disease progression most develop pyramidal signs suggestive of motor neuron disease, with a mean disease duration of roughly 46 months. Valine/valine (VV) carriers, who are younger on average at about 63.5 years, tend to present with cognitive and psychiatric symptoms overlapping with frontotemporal dementia, and later develop combined extrapyramidal and cerebellar features. Heterozygous MV carriers often begin with psychiatric and extrapyramidal symptoms but have the shortest average disease duration at around 22.5 months.

The first new case illustrates how bewildering the clinical picture can become. An 86-year-old woman with an MM genotype was referred for atypical parkinsonism with right-sided bradykinesia that did not respond to levodopa. She had experienced gait disturbance and frequent falls for seven years, along with memory problems and urinary incontinence. Examination revealed mild rigidity, postural instability, diffuse muscle weakness, dysarthria and a vertical gaze palsy, and a MoCA test confirmed significant cognitive impairment. Her cerebrospinal fluid showed normal 14-3-3 protein, a negative RT-QuIC assay and normal Alzheimer biomarkers. Brain MRI suggested normal pressure hydrocephalus, and because lumbar puncture temporarily alleviated some symptoms, a shunt was considered. Before surgery could happen, she deteriorated with personality changes, apathy, global aphasia and non-convulsive status epilepticus with myoclonus, and died after a total disease duration of roughly seven years.

Postmortem examination of her brain revealed a striking mixture of pathologies. Focal, mild spongiform change was present in the frontal and temporal cortex, basal ganglia and hippocampus, with the pre- and postcentral regions particularly affected, showing neuronal loss, gliosis and degeneration of the descending corticospinal tract. Immunohistochemistry for the disease-related prion protein revealed fleecy and freckled deposits over a faint synaptic staining pattern in cortical areas and the hippocampus, with focal intraneuronal granular deposits in the thalamus. Remarkably, the cerebellum was completely devoid of prion protein immunoreactivity, even after repeated staining with two different antibodies. Alongside the prion pathology, the team found abundant 4-repeat tau-positive grains consistent with argyrophilic grain disease at stage III, mild limbic-predominant age-related TDP-43 encephalopathy (LATE), mild Alzheimer disease neuropathologic changes, and diffuse small vessel disease. Western blot analysis of frozen cortical tissue confirmed the VPSPr signature: a 19 kDa prion protein fragment virtually devoid of the diglycosylated form, plus two additional truncated fragments, while the cerebellum was negative, matching the histology.

The second patient, a 69-year-old woman with a VV genotype, presented very differently. She developed subtle progressive cognitive decline from June 2021, and by late 2022 her memory impairment had worsened alongside prominent word-finding and naming difficulties and trouble following conversations. Brain MRI showed ventricular enlargement without cortical or basal ganglia hyperintensities, the EEG showed no triphasic waves, and the RT-QuIC assay was twice negative. Yet 14-3-3 protein in her cerebrospinal fluid was elevated on two measurements, raising clinical suspicion of CJD despite the atypical overall picture. She progressed to tetraplegia and dysphagia and died after about 3.5 years. Her autopsy showed the characteristic VPSPr morphology, including fleecy and freckled cortical deposits, granular deposits in large cholinergic neurons of the basal ganglia, and, in contrast to the first case, characteristic ill-defined coarse deposits, pseudo-plaques and microplaques in the cerebellar molecular layer. No additional protein aggregates were identified, making this a purer single-pathology case.

The contrast between the two cases highlights how the codon 129 polymorphism sculpts both clinical presentation and brain distribution of disease. The authors argue that detailed histotyping, as routinely performed for sCJD, could be useful in VPSPr as well: a laminar prion protein deposition pattern and intraneuronal granular deposits may suggest the valine genotype, while prominent involvement of the pyramidal system may predict methionine. Previous reports support these associations, with some MM patients presenting with motor neuron disease-like syndromes and neuropathological evidence of motor system involvement, including degeneration of the pyramidal tracts. The absence of cerebellar prion deposits in the first patient made the diagnosis particularly challenging, and the authors note that cerebellar sparing appears to be influenced by the presence of methionine at codon 129, with prior western blot data indicating that resistance to proteinase K digestion is lowest in VV cases and highest in MM cases.

Several deeper biological puzzles remain. The western blot pattern of VPSPr, with its characteristic low molecular weight 7 kDa fragment, resembles that seen in Gerstmann-Sträussler-Scheinker disease, an inherited prion protein amyloidosis, leading some researchers to propose that VPSPr represents the sporadic counterpart of that genetic disorder. Another striking discrepancy is that most VPSPr cases show only mild spongiform change despite severe neurological symptoms, which the authors attribute to the reduced seeding potency of the abnormal prion protein and to early toxic oligomer-mediated disruption of synaptic transmission, a process that can cripple neural circuits before neuronal loss becomes visible under the microscope. The team also cautions that the fleecy and freckled staining pattern of VPSPr can mimic nonspecific staining of beta-amyloid-related senile plaques in Alzheimer disease, although VPSPr microplaques lack classical amyloid characteristics and are negative for beta-amyloid, Congo red and thioflavin S.

For clinicians, the message is clear: VPSPr belongs in the differential diagnosis of rapidly progressive and atypically progressive neurological diseases, including cases within the frontotemporal lobar degeneration and motor neuron disease spectrum, especially in elderly patients whose biomarkers are inconclusive and who carry overlapping co-pathologies. As the population ages and mixed proteinopathies become increasingly common at autopsy, recognizing this rare prion disorder amid the noise of tau, TDP-43 and amyloid accumulation will remain one of neuropathology’s most demanding diagnostic challenges.

Subject of Research: Variably protease-sensitive prionopathy, a rare sporadic human prion disease, and its diagnostic challenges in the context of co-existing neurodegenerative pathologies

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

Article References: Simonovska Serra, A., Vargiu, C. M., Klotz, S., Berger-Sieczkowski, E., Kreiter, M., Leoni, M., Guttmann-Lattmanig, A., Haider, L., Regelsberger, G., Parchi, P., & Gelpi, E. (2026). Variably protease-sensitive prionopathy in the context of a complex proteinopathy: clinical and neuropathological challenges. Frontiers in Neuroscience, 20, Article 1950078. https://doi.org/10.3389/fnins.2026.1950078

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1950078

Keywords: VPSPr, prion disease, Creutzfeldt-Jakob disease, PRNP codon 129, frontotemporal lobar degeneration, motor neuron disease, argyrophilic grain disease, LATE, TDP-43, western blot, neuropathology, proteinase K