Demyelinating polyneuropathy in goats lacking prion protein

Abstract

Studies in mice with ablation of Prnp, the gene that encodes the cellular prion protein (PrP C ), have led to the hypothesis that PrP C is important for peripheral nerve myelin maintenance. Here, we have used a nontransgenic animal model to put this idea to the test; namely, goats that, due to a naturally occurring nonsense mutation, lack PrP C .Teased nerve fiber preparation revealed a demyelinating pathology in goats without PrP C . Affected nerves were invaded by macrophages and T cells and displayed vacuolated fibers, shrunken axons, and onion bulbs. Peripheral nerve lipid composition was similar in young goats with or without PrP C , but markedly different between corresponding groups of adult goats, reflecting the progressive nature of the neuropathy. This is the first report of a subclinical demyelinating polyneuropathy caused by loss of PrP C function in a nontransgenic mammal. K E Y W O R D Slipidomic, myelin, neuropathy, PRNP haplotype 2360 |

Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

“…measured in sciatic nerve lysates by western blotting (Fig 3A and 3B). FT injected mice showed a significant increase in the levels of pAKT after 30 minutes (relative pAKT change based on quantitative analysis of western blots: control 1.00 ± 0.05(3); FT 1.53 ± 0.11 (3); p = 0.0116; mean ± SEM(n); unpaired t-test), whereas FT 2 Fc did not elicit an acute increase Fig 3. Establishment of readout and pharmacokinetics.…”

“…Yet the remarkable evolutionary conservation of PrP suggests that it exerts physiological functions. Mice ablated for PrP [1,2] and goats lacking PrP due to a naturally occurring mutation [3] develop a progressive peripheral demyelinating neuropathy, indicating that PrP is involved in myelin maintenance. Although no mutations in the human PRNP gene were found in a study of patients with hereditary neuropathies [4], the alteration of PrP or its sequestration in aggregates could explain the development of peripheral neuropathy in patients suffering from Creutzfeldt-Jakob disease [5].…”

Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints

“…Knockout animals are healthy ( 11–13 ). The only established knockout phenotype is a peripheral neuropathy, apparently due to deficiency of myelin maintenance signaling to a Schwann cell receptor ( 14 ), which is histologically evident yet phenotypically mild to undetectable in homozygotes and is not observed in heterozygotes ( 15 , 16 ). Heterozygous inactivating mutations also appear to be tolerated in humans ( 17 , 18 ), minimizing any concern about on-target toxicity of pharmacologic PrP lowering.…”

Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints

“…Knockout animals are healthy [11][12][13] . The only established knockout phenotype is a peripheral neuropathy, apparently due to deficiency of myelin maintenance signaling to a Schwann cell receptor 14 , which is histologically evident yet phenotypically mild to undetectable in homozygotes and is not observed in heterozygotes 15,16 . Heterozygous inactivating mutations also appear to be tolerated in humans 17,18 , minimizing any concern about on-target toxicity of pharmacologic PrP lowering.…”