Thursday, August 19, 2010

New Sporadic Prion Protein Disease Identified by Case Western Reserve

A new sporadic prion protein disease has been discovered. Variably protease-sensitive prionopathy (VPSPr), as it has been named, is the second type of complete sporadic disease to be identified since Creutzfeldt-Jakob disease (CJD) was reported in the 1920s. The landmark finding from the National Prion Disease Pathology Surveillance Center at Case Western Reserve University is published in the August issue of Annals of Neurology

In 2008, Pierluigi Gambetti, MD (pictured), and Wen-Quan Zou, MD, PhD, with collaborators, reported the discovery of this novel disease, which affected patients who exhibit only one of the three types of the prion protein gene. In this follow-up study, they discovered that all three genetic groups can be affected also by this novel disease which now joins sCJD in displaying this feature. However, VPSPr is associated with an abnormal prion protein that exhibits characteristics very different from those of sCJD, as well as other prion diseases, suggesting that it may be caused by a different mechanism, perhaps more akin to other neurodegenerative diseases, such as Alzheimer’s disease. This finding may exemplify, for the first time, the possibility that the prion protein affects the brain with different mechanisms.

While examining cases received at the National Prion Disease Pathology Surveillance Center where he is the director, Dr. Gambetti observed that a subset of cases had clinical and pathological features quite different from those of all known types of human prion diseases. Further, after being tested for prion proteins via the Western blot – the gold standard of prion disease diagnosis – the cases were negative. Dr. Gambetti then collaborated with Dr. Zou, associate director at the center, to solve the riddle of a disease that exhibited some features of a prion disease in histopathological examination but was negative using the standard Western blot test.

Dr. Zou’s lab performed a full characterization of the disease and discovered that the VPSPr-associated abnormal prion protein formed a ladder-like electrophoretic profile on Western blot. “When I obtained the first Western blot result of these cases with a different antibody against prions, I was surprised that these cases consistently exhibited this particular profile; one that I had never seen in my more than 10 years of work on human prion diseases,” Dr. Zou, assistant professor of pathology at Case Western Reserve School of Medicine, recalls. This ladder-like profile is quite distinctive and very different from the profile of common prion diseases. “Discovery of this unique type of prion provides solid evidence that this novel disease may possess a pathogenesis that is different from that of the major prion diseases currently known,” Dr. Zou adds.

Despite extensive research, a relatively large group of neurodegenerative diseases associated with dementia remain undefined. The discovery of VPSPr is chipping away at that group. In the two years since its discovery, more than 30 cases have been reported.

“If, as the current evidence indicates, the VPSPr mechanism of affecting the brain is different from that of other sporadic prion diseases, such as sCJD, the discovery of VPSPr would also provide the first example that the prion protein may spontaneously damage the brain with different mechanisms,” concludes Dr. Gambetti, professor of pathology at Case Western Reserve School of Medicine. “This might apply to other dementing illnesses as well, and has implications for the strategies that need to be followed to attain a cure.”

Drs. Gambetti and Zou, along with their extensive research team, plan to further characterize the abnormal prion protein associated with VPSPr as well as other important features of the protein, such as the disease’s propensity for transmission upon inoculation and its replication in test tubes. These features in VPSPr will be compared with those of sCJD to obtain a complete picture of how the abnormal prion protein attacks the brain in these two diseases.

This research was supported by funding from the National Institutes of Health, Centers for Disease Control and Prevention, Britton Fund, CJD Foundation, Alliance BioSecure, and University Center on Aging and Health with the support of the McGregor Foundation, and President’s Discretionary Fund (Case Western Reserve University).


Anonymous said...

Perhaps histopathology still trumps Western Blot? Is this really the "gold standard" of CJD and other prion disease diagnosis? I'm a bit of an iconoclast on this subject; I've always felt that with good quality histology classical spongiform change (as carefully described and defined by Masters and Richardson) with neuronal loss and gliosis limited to gray matter structures was the real gold standard.

Anonymous said...

Monday, August 9, 2010

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?

Saturday, August 14, 2010

BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY

(see mad cow feed in COMMERCE IN ALABAMA...TSS)

Thursday, August 12, 2010

Seven main threats for the future linked to prions

Wednesday, August 18, 2010

Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010

Monday, August 9, 2010

National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)

(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)

Anonymous said...

Too bad autopsy and biopsy rates in this country remain comparatively low. Too bad the focus of the NPDPSC has been on pathology and not epidemiology as is reflected by their extremely limited fill-in-the-blank intake questionnaire and failure to interview family members.
Odd how we observe the other members of the animal kingdom so closely and expect to further our understanding of human prion disease by looking at brain tissue only... and only in such a limited number of cases.
If today we looked at sporadic CJD the way NIH doctors did Kuru(eager and willing to look at all presenting cases in the tribe), maybe that definitive ante mortem biological screening marker would have been a done deal by now... with an anonymous iconoclast the creator.

The link to a recent study by Emory posted below has me concerned. Will your neurology department and institution actively support autopsy efforts or will these levels drop?
Families of U.S. victims have reported that they were actually advised not to seek autopsy or in some instances were not even told that CJD was a likely diagnosis let alone advised to seek autopsy. The 2006 study entitled Barriers to Autopsy: Creutzfeldt-Jakob Disease in New York State states in their abstract: "Neurologists reported using autopsy rarely or never. Over half of the pathologists worked in facilities that did not perform autopsies when CJD was suspected." Interesting approach to disease recognition and management in a country where the last published studies on the risk factors of sCJD were from 1985-86.

Wouldn't it be nice to know where the "tip of the iceberg" might be floating?