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 2-3 and 2-2 loops of PrP C . Importantly, GDL that suppresses the Hlatch 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 19 individual PrP C variants to PrP C -deficient cerebellar organotypic cultured slices using adenovirusassociated 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 wildtype PrP C . K 27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.
The cellular prion protein PrPC mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrPC (GDL) can also initiate neurotoxicity by inducing an intramolecular R208-H140 hydrogen bond (H-latch) between the alpha2-alpha2 and beta2-alpha2 loops of PrPC. 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 PrPC variants to PrPC-deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K27 or R27) within PrPC. Alanine substitution of K27 also prevented the toxicity of PrPC mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrPC. K27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.
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