# Substitution of histidine 95 by tyrosine in the prion protein causes spontaneous neurodegeneration in transgenic mice

## TL;DR

Changing a specific amino acid in the prion protein causes spontaneous neurodegeneration in mice, suggesting a link between copper binding and prion disease.

## Contribution

A novel transgenic mouse model with a PrP H95Y mutation shows spontaneous prion disease and disease transmission.

## Key findings

- Transgenic mice with PrP H95Y mutation develop lethal prion disease with spongiform degeneration.
- Brain homogenates from PrP H95Y mice transmit disease to wild-type PrP mice.
- Copper coordination disruption at H95 promotes PrPC to PrPSc conversion in vivo.

## Abstract

Prion diseases are neurodegenerative disorders caused by a change in conformation of the prion protein from the cellular form (PrPC) to a misfolded isoform (PrPSc). PrPC is a copper binding protein via histidine residues in the octapeptide repeats (OR) and the non-OR region located at the N-terminus. Although the functional implication of copper binding to PrPC is still under investigation, copper may play a role in prion disease. In this study, we describe transgenic mice expressing mouse prion protein replacing histidine 95 by tyrosine (PrP H95Y) to disrupt the non-OR copper-binding site. Transgenic mice overexpressing PrP H95Y showed clinical signs and died at about 100 days with spongiform degeneration and PK-resistant PrP. Inoculation of brain homogenate from mice overexpressing PrP H95Y to Tga20 mice expressing wild-type PrP also causes lethal, spongiform encephalopathy. We conclude that this substitution could promote PrPC-PrPSc conversion and induce spontaneous prion disease in vivo.

Prion diseases are neurodegenerative disorders characterized by the misfolding of the normal cellular prion protein (PrPC) into a pathogenic isoform (PrPSc). PrPC binds copper through histidine residues located in the N-terminal domain, and copper binding has been proposed to influence PrPC structure and its conversion to PrPSc. In this study, we aimed at disrupting this copper coordination by generating transgenic mice expressing a mutant prion protein, in which histidine 95 was replaced by tyrosine (PrP H95Y). Mice overexpressing PrP H95Y developed spontaneous prion disease with typical clinical signs, spongiform degeneration, and protease-resistant PrP accumulation. Furthermore, brain homogenates from these mice were able to transmit the disease to mice expressing wild-type PrP, validating the infectious nature of the spontaneously generated prions. These results demonstrate that interfering with copper coordination at H95 is sufficient to promote prion conversion in vivo, further highlighting the connection between copper binding and prion pathogenesis.