Mechanism of Prion Protein (PrP) Degradation Induced by a Tetracationic-porphyrin: Implications for the Therapy of Prion Diseases

Masone, Antonio (2023). Mechanism of Prion Protein (PrP) Degradation Induced by a Tetracationic-porphyrin: Implications for the Therapy of Prion Diseases. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00016206

Abstract

Prions are infectious agents responsible for deadly brain diseases. They consist of scrapie prion protein (PrP^Sc), a misfolded variant of the plasma membrane cellular prion protein (PrP^C) which self-propagates by inducing misfolding of native PrP^C. One of the multiple reasons that hampers the development of effective therapies, is that prions can adopt different pathogenic conformations (strains), which can be resistant to potential drugs, or acquire drug resistance during treatment. PrP^C is the precursor and the substrate for the replication of any prion strain, and therefore represents the ideal target to abrogate prion generation and propagation in a strain-independent fashion. There is ample experimental evidence available that lowering PrP^C is well tolerated and highly beneficial in prion disease, suggesting that targeting PrP^C could be a promising therapeutic strategy.

This thesis describes Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of PrP^C in a metal-dependent fashion, promoting PrP^C degradation while inhibiting its conversion to PrP^Sc. Zn(II)-BnPyP binding to a C-terminal pocket destabilises the native PrP^C fold, hindering conversion to PrP^Sc; Zn(II)-BnPyP binding to the flexible N-terminal tail disrupts N- to C-terminal interactions, triggering PrP^C endocytosis and lysosomal degradation, thus reducing the substrate for PrP^Sc generation. With its bimodal action on the prion precursor protein, Zn(II)-BnPyP efficiently inhibits propagation of different prion strains in vitro, in neuronal cells and organotypic brain cultures, curing prion infection. These results identify a PrP^C-targeting anti-prion compound with an unprecedented mechanism of action which should evade the problem of drug resistance.