In Creutzfeldt-Jakob disease (CJD), the type (type 1 and type 2) of abnor- mal isoform of prion protein (PrP^^) in the brain and the genotype at codon

Type 1 and type 2 human PrP^^ have different aggregation sizes in methionine homozygotes with sporadic, iatrogenic and variant Creutzfeidt-Jakob disease

Atsushi Kobayashi\ Sakae Satoh^, James W. Ironside^ Shirou Mohri"^ and Tetsuyuki Kitamoto^

^Division of CJD Science and Technology, Department of Prion Research, Center for Translational and Advanced Animal Research on Human Dis- eases, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai 980-8575 Japan ^Planova Division, Asahi Kasei Pharma Corporation, Tokyo, Japan ^National Creutzfeldt-Jakob Disease Surveillance Unit, Division of Pathology, University of Edinburgh, West- em General Hospital, Edinburgh, UK "^Laboratory of Biomedicine, Cen- ter of Biomedical Research, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan <e-mail> kobayashi@mail.tains.tohoku.ac.jp

Abstract

In Creutzfeldt-Jakob disease (CJD), the type (type 1 and type 2) of abnor- mal isoform of prion protein (PrP^^) in the brain and the genotype at codon

129 of the PrP gene are major determinants of the clinicopathological phenotype. Type 1 and type 2 PrP^^ are distinguished by the size of pro- teinase K (PK) resistant core (21 and 19 kDa), reflecting differences in the PK-cleavage site. Moreover, type 2 PrP^^ can be subclassified into type 2A and type 2B by the difference in ratio of glycoforms. However, little is known about the difference in biochemical properties between the two types of PrP^^, exept for the different PK-cleavage sites. On the basis of these findings, we hypothesized that (1) type 1 and type 2 PrP^^ may have distinct aggregation sizes and (2) PrP^^ from a patient with PrP amyloid plaques in the brain has a larger aggregation size than PrP^^ from a patient with synaptic non-amyloid type PrP deposits in the brain.

To clarify the difference in aggregation size, we filtered brain homoge- nates from various cases of CJD with the same genotype (homozygous for methionine at codon 129; type 1, type 2A, type 2B and both type 1 and

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type 2 PrP^^ coexisting; with or without amyloid plaques) through virus removal filters of mean pore size 72 ± 4 nm.

Type 2 PrP^^ was efficiently removed from the filtrates by the filters in contrast to type 1. Even type 2 PrP^"^ from a patient without amyloid plaques was removed more efficiently than type 1 from patients with amyloid plaques. In the brain samples both types of PrP^^ coexisting, type 2 was removed by filtration more efficiently than type 1 under the same conditions.

These results suggest that type 1 PrP^'^ aggregates are generally of small

size, while type 2 PrP^^ aggregates are all of a larger size and do not con-

tain a fraction of small-sized aggregates. The present study indicate that

type 2 PrP^"" has a larger aggregation size than type 1, irrespective of the

existence of amyloid plaques.