Uncovering the variability and regulation of PRNP gene and their relevance in chronic wasting disease susceptibility and transmission

Transmissible spongiform encephalopathies (TSEs), more commonly referred to as prion diseases, constitute a group of neurodegenerative and fatal disorders that impact various mammalian species. The pathogenic isoform responsible for these diseases is PrPSc, derived from the cellular prion protein, PrPC. The conversion of PrPC into PrPSc can manifest spontaneously or through induction by an external agent, leading to acquired cases. Notably, amino acid substitutions or polymorphisms in the PrP protein play a pivotal role in influencing the misfolding process. The intricate landscape of PrP polymorphisms is marked by their association with spontaneous misfolding and their link to the development of familial or hereditary forms of prion diseases. In cases of acquired prion diseases, variations in amino acids between the PrPC in the host and the PrPSc in the donor contribute to modifying prion strain characteristics during transmission. This alteration impacts the transmission barrier, thereby influencing the host range. Heightened concerns revolve around the potential emergence of novel cervid prion strains capable of surmounting transmission barriers and infecting humans. Chronic wasting disease (CWD), a prion disorder affecting cervids, has attained widespread prevalence in the USA and Canada. Notably, cases have been documented in South Korea, and the disease has recently been identified in Norway, Finland, and Sweden. The considerable horizontal transmission capacity of CWD, combined with the diverse polymorphisms present in cervid PrP, heightens the prospect of new prion strain emergence, as evidenced by strains identified in Northern Europe. Vigilant monitoring and a nuanced understanding of these dynamic processes are imperative for effectively addressing the evolving challenges posed by prion diseases. This study aims to characterize the prevalent polymorphisms and identify novel variants within the coding sequence of the prion protein gene (PRNP) in the Portuguese deer population, encompassing red deer (Cervus elaphus), fallow deer (Dama dama), and roe deer (Capreolus capreolus). The primary objective was to unveil distinctive polymorphic variants intricately linked to susceptibility to CWD. In red deer, specific amino acid variants, p.98T>A, p.138S>N, and p.226Q>E, have been identified. These findings contribute to a nuanced understanding of the intricate genetic landscape underlying the susceptibility profile of the studied cervid population, shedding light on potential factors influencing CWD susceptibility in this specific context. Simultaneously, a lack of sequence variation was observed in fallow deer. However, unexpectedly, the results from roe deer population confirmed a new genetic variant in PRNP gene coding sequence, denoted as p.85G>E and , at same time, unveiled 10 haplotypes through mitochondrial DNA molecular analysis, proving the variability of this group. Running parallel to this path, this research incorporated the application of real-time quaking-induced conversion (RT-QuIC) assays to evaluate prion infection. Traditionally, recombinant hamster and bank vole prion proteins have demonstrated efficacy as substrates for North American strains. However, our investigation extended beyond convention to assess the adaptability of these substrates to novel European CWD strains. We compared their performance with potential alternative substrates for RT-QuIC assays, using diverse genetic variants of cervid prion proteins. The outcomes of our study unveiled a more robust and efficient substrate for conducting RT-QuIC assays, enabling the identification of both European and North American CWD strains. This advancement represents a notable enhancement in the methodology, promising increased accuracy, and reliability in the detection of infected animals with different strains. Furthermore, this research project successfully established a transgenic mouse model, providing a platform to investigate the spontaneous or acquired aspects of CWD. This transgenic model was created by integrating cutting-edge methodologies, specifically employing CRISPR-Cas9 technology, which allowed the precise editing of specific genetic sequences. Moreover, this new generated model, along with this technology, will facilitate the introduction of genetic variations associated with CWD susceptibility in a more controlled and efficient manner. Thus, it will enable the establishment of new transgenic models that closely mimic the genetic variations observed in affected species, thereby facilitating the investigation of disease mechanisms and the exploration of potential therapeutic interventions.

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