Work

Rapid ex vivo reverse genetics identifies the essential determinants of prion protein toxicity

Year: 2022

Type: article

Abstract: The cellular prion protein PrP C mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrP C (GDL) can also initiate neurotoxicity by inducing an intramolecular R 208 -H 140 hydrogen bond (“H-latch”) between the α2-α3 and β2-α2 loops of PrP C . Importantly, GDL that suppress the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced nineteen individual PrP C variants to PrP C -deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K 27 or R 27 ) within PrP C . Alanine substitution of K 27 also prevented the toxicity of PrP C mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrP C . K 27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.

Source: Brain Pathology

DOI: 10.1111/bpa.13130