A novel human disease with abnormal prion protein sensitive to protease.
OBJECTIVE
To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion.


METHODS
Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and PrP characteristics.


RESULTS
Patients presented with behavioral and psychiatric manifestations on average at 62 years, whereas mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern, and the presence of microplaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. After enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly 4 times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the National Prion Disease Pathology Surveillance Center. Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame.


CONCLUSIONS
The distinct histopathological, PrP immunohistochemical, and physicochemical features, together with the homogeneous genotype, indicate that this is a previously unidentified type of disease involving the PrP, which we designated "protease-sensitive prionopathy" (or PSPr). Protease-sensitive prionopathy is not rare among prion diseases, and it may be even more prevalent than our data indicate because protease-sensitive prionopathy cases are likely also to be classified within the group of non-Alzheimer's dementias.
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. pxg13@case.edu
Pierluigi
P
Gambetti
Zhiqian
Z
Dong
Jue
J
Yuan
Xiangzhu
X
Xiao
Mengjie
M
Zheng
Amer
A
Alshekhlee
Rudy
R
Castellani
Mark
M
Cohen
Marcelo A
MA
Barria
D
D
Gonzalez-Romero
Ermias D
ED
Belay
Lawrence B
LB
Schonberger
Karen
K
Marder
Carrie
C
Harris
James R
JR
Burke
Thomas
T
Montine
Thomas
T
Wisniewski
Dennis W
DW
Dickson
Claudio
C
Soto
Christine M
CM
Hulette
James A
JA
Mastrianni
Qingzhong
Q
Kong
Wen-Quan
WQ
Zou
D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003704:Dementia / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D011328:Prions / Q000032:analysis* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D011328:Prions; D010447:Peptide Hydrolases