Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism

Abstract

The majority of bovine spongiform encephalopathy (BSE) cases have been ascribed to the classical form of the disease. H-type and L-type BSE cases have atypical molecular profiles compared to classical BSE and are thought to arise spontaneously. However, one case of H-type BSE was associated with a heritable E211K mutation in the prion protein gene. The purpose of this study was to describe transmission of this unique isolate of H-type BSE when inoculated into a calf of the same genotype by the intracranial route. Electroretinograms were used to demonstrate preclinical deficits in retinal function, and optical coherence tomography was used to demonstrate an antemortem decrease in retinal thickness. The calf rapidly progressed to clinical disease (9.4 months) and was necropsied. Widespread distribution of abnormal prion protein was demonstrated within neural tissues by western blot and immunohistochemistry. While this isolate is categorized as BSE-H due to a higher molecular mass of the unglycosylated PrPSc isoform, a strong labeling of all 3 PrPSc bands with monoclonal antibodies 6H4 and P4, and a second unglycosylated band at approximately 14 kDa when developed with antibodies that bind in the C-terminal region, it is unique from other described cases of BSE-H because of an additional band 23 kDa demonstrated on western blots of the cerebellum. This work demonstrates that this isolate is transmissible, has a BSE-H phenotype when transmitted to cattle with the K211 polymorphism, and has molecular features that distinguish it from other cases of BSE-H described in the literature.

Stability properties of PrPScfrom cattle with experimental transmissible spongiform encephalopathies: use of a rapid whole homogenate, protease-free assay

“…In a separate experiment, BSE-infected E211K brain homogenate (obtained from the 2006 U.S. BSE case [23]) was IC inoculated into a EK 211 heterozygous calf (Animal #25); complete details of the experiment and the histopathology of calf #25 were described previously [28]. Experimental infection of a wild-type calf (Animal #26) with classical BSE brain homogenate was completed in parallel by IC inoculation.…”

Temporal Resolution of Misfolded Prion Protein Transport, Accumulation, Glial Activation, and Neuronal Death in the Retinas of Mice Inoculated with Scrapie

“…The retina is part of the CNS and is affected by numerous protein misfolding diseases, including Alzheimer disease, 9 Parkinson disease, 10e12 and numerous TSEs, including scrapie in sheep, 13,14 chronic wasting disease in cervids, 15e17 bovine spongiform encephalopathy in cattle, 18,19 and Creutzfeldt-Jakob disease in humans. 20,21 The retina and associated visual structures provide an excellent model to study the transport of misfolded proteins from one CNS structure to another.…”

A Review of Selected Genes with Known Effects on Performance and Health of Cattle

“…Although believed to be extremely rare (94), one H-type BSE case (95) was associated with a heritable E211K mutation in the prion protein gene ( PRNP ) and is now thought to represent the bovine ortholog of the most common form of genetic CJD (E200K) in humans (96). Intracranial inoculation of infected brain material from the E211K BSE case into cattle possessing the 211K allele has demonstrated a very rapid onset of clinical BSE, consistent with a genetic form of BSE (97). A comprehensive review is available (98).…”