Overexpression of bank vole PrP(I109) in mice induces a spontaneous atypical prion disease with sex- dependent onset, early NfL elevation, and universal prion strain permissiveness

Transgenic mice overexpressing bank vole prion protein with the isoleucine 109 polymorphism TgVole(I109)4x develop spontaneous neurodegenerative disease with sex-dependent onset, averaging 170 days in females and 200 days in males at terminal stage. The clinical and pathological features closely resemble Gerstmann-Sträussler-Scheinker syndrome (GSS), with characteristic ataxia, dysmetria, kyphosis, and prominent PrP plaques. Biochemical analysis reveals an atypical prion protein banding pattern with a distinctive low molecular weight band (7–10 kDa) following proteinase K digestion, similar to other atypical prion diseases such as small ruminants atypical scrapie (AS). Importantly, these spontaneously generated prions are highly infectious when passaged to mice expressing the same I109 polymorphism as well as to wild bank voles carrying the I109 polymorphism, but not to models expressing the methionine variant at this position, demonstrating the critical role of this specific polymorphism in atypical prion propagation. Temporal analysis reveals that infectious prions emerge significantly (2–3 months) before clinical signs appear, offering important insights into the pre-clinical phase of prion diseases. Serum neurofilament light chain levels increase significantly at 80 days of age, approximately 100 days before clinical onset, providing a wide therapeutic window with a reliable biomarker. The TgVole(I109)4x model exhibits extraordinary versatility in propagating diverse prion strains, showing remarkable susceptibility to atypical prions (including GSS and AS) with exceptionally short incubation periods, while maintaining the ability to efficiently propagate classical and recombinant prion strains.We present here a thoroughly characterized transgenic mouse model that spontaneously develops an atypical, bona fide prion disease with sex-related differences in disease onset. This model offers valuable insights into spontaneous and atypical prionopathies while demonstrating exceptional versatility for studying diverse prion strains and evaluating therapeutic interventions.Author SummaryPrion diseases are fatal brain disorders caused when a normal protein misfolds into a harmful form. Our study characterizes a transgenic mouse model expressing bank vole prion protein with the isoleucine 109 polymorphism that spontaneously develops a prion disease sharing key features with human Gerstmann-Sträussler-Scheinker syndrome and small ruminants atypical scrapie, also known as Nor98. We found that female mice consistently develop symptoms about 30 days earlier than males, revealing an important sex difference in disease progression. The spontaneously generated prions are highly infectious, transmitting disease efficiently to mice expressing the same I109 polymorphism but not to mice with the methionine variant, highlighting this residue's critical role in atypical prion propagation. Infectivity emerges 2–3 months before clinical signs appear, providing insight into the preclinical phase of prion diseases. The model shows exceptional susceptibility to atypical prion strains while maintaining versatility in propagating classical prions. Importantly, we identify neurofilament light chain as an early biomarker that increases significantly about 100 days before clinical signs, providing a wide therapeutic window for evaluating potential interventions. This model fills a critical gap in prion research by providing a reliable system to study how prion diseases develop naturally and to test potential treatments with an early warning biomarker.