Autor(es): Frontzek, K ; Bardelli, M ; Senatore, A ; Henzi, A ; Reimann, RR ; Bedir, S ; Marino, M ; Hussain, R ; Jurt, S ; Meisl, G ; Pedotti, M ; Mazzola, F ; Siligardi, G ; Zerbe, O ; Losa, M ; Knowles, T ; Lakkaraju, A ; Zhu, C ; Schwarz, P ; Hornemann, S ; Holt, MG ; Simonelli, L ; Varani, L ; Aguzzi, A
Data: 2022
Identificador Persistente: https://hdl.handle.net/10216/165533
Origem: Repositório Aberto da Universidade do Porto
Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity.
