Molecular Medicine News

 

The first issue of a new journal "Intrinsically Disordered Proteins" with Dr. Uversky as an Executive Editor is published by Landes Bioscience

 

The issue is published online here: Landes Bioscience.

Journal Cover


 

Dickey

Molecular Medicine News

 

Chad Dickey, PhD
Associate Professor
Molecular Medicine and USF Health Byrd Alzheimer's Institute

USF-led study suggests FKBP51 is a new treatment target for diseases with tau pathology

Tampa, FL (Sept. 3, 2013) – A stress-related protein genetically linked to depression, anxiety and other psychiatric disorders contributes to the acceleration of Alzheimer’s disease, a new study led by researchers at the University of South Florida has found.

The study is published online today in the Journal of Clinical Investigation.


When the stress-related protein FKBP51 partners with another protein known as Hsp90, this formidable chaperone protein complex prevents the clearance from the brain of the toxic tau protein associated with Alzheimer’s disease.

Under normal circumstances, tau helps make up the skeleton of our brain cells. The USF study was done using test tube experiments, mice genetically engineered to produce abnormal tau protein like that accumulated in the brains of people with Alzheimer’s disease, and post-mortem human Alzheimer’s brain tissue.

The researchers report that FKBP51 levels increase with age in the brain, and then the stress-related protein partners with Hsp90 to make tau more deadly to the brain cells involved in memory formation.

Hsp90 is a chaperone protein, which supervises the activity of tau inside nerve cells. Chaperone proteins typically help ensure that tau proteins are properly folded to maintain the healthy structure of nerve cells.

However, as FKBP51 levels rise with age, they usurp Hsp90’s beneficial effect to promote tau toxicity.

“We found that FKB51 commandeers Hsp90 to create an environment that prevents the removal of tau and makes it more toxic,” said the study’s principal investigator Chad Dickey, PhD, associate professor of molecular medicine at the USF Health Byrd Alzheimer’s Institute. “Basically, it uses Hsp90 to produce and preserve the bad tau.”

The researchers conclude that developing drugs or other ways to reduce FKB51 or block its interaction with Hsp90 may be highly effective in treating the tau pathology featured in Alzheimer’s disease, Parkinson’s disease dementia and several other disorders associated with memory loss.

A previous study by Dr. Dickey and colleagues found that a lack of FKBP51 in old mice improved resilience to depressive behavior.

The latest study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

 

Article citation:
“Accelerated neurodegeneration through chaperone-mediated oligomerization of tau;” Laura J. Blair, Bryce A. Nordhues, Shannon E. Hill, K. Matthew Scaglione, John C. O’Leary III, Sarah N. Fontaine, Leonid Breydo, Bo Zhang, Pengfei Li, Li Wang, Carl Cotman, Henry L. Paulson, Martin Muschol, Vladimir N. Uversky, Torsten Klengel,Elisabeth B. Binder, Rakez Kayed, Todd E. Golde, Nicole Berchtold, and Chad A. Dickey; Journal of Clinical Investigation, Vol. 123, No. 10. DOI:10.1172/JCI69003.



-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50thin the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities.

Media contact:
Anne DeLotto Baier, USF Health Communications
(813) 974-3303, or abaier@health.usf.edu


Pantry Success

Molecular Medicine News

 

Congratulations: Shara Pantry

Major Professor:

Peter Medveczky , MD
Professor
Tumor virology

The work of Shara Pantry who will defend her PhD dissertation in a few weeks is an important scientific milestone for several reasons. Many experts believe that chronic fatigue syndrome (CFS) has several root causes including some viruses. Now, lead scientists Shara Pantry, Maria Medveczky and Peter Medveczky of the University of South Florida’s Morsani College of Medicine, along with the help of several collaborating scientists and clinicians, have published an article in the Journal of Medical Virology suggesting that a common virus, Human Herpesvirus 6 (HHV-6), is the possible cause of some CFS cases. This article represents a component of Shara’s PhD dissertation defense although she has more data yet to be published.

The link between HHV-6 infection and CFS is quite complex. After the first encounter, or “primary infection,” all nine known human herpesviruses become silent, or “latent,” but may reactivate and cause diseases upon immunosuppression or during aging. Over 95 percent of the population is infected with HHV-6 by age 3, but in those with normal immune systems the virus remains inactive. HHV-6 causes fever and rash (or roseola) in infants during early childhood, and is spread by saliva. In immunocompromised patients, it can reactivate to cause neurological dysfunction, encephalitis, pneumonia and organ failure. A previous study from the laboratory showed that HHV-6 is unique among human herpesviruses; during latency, its DNA integrates into the structures at the end of chromosomes known as telomeres. Furthermore, this integrated HHV-6 genome can be inherited from parent to child, a condition commonly referred to as “chromosomally integrated HHV-6,” or CIHHV-6. By contrast, the “latent” genome of all other human herpesviruses converts to a circular form in the nucleus of the cell, not integrated into the chromosomes, and not inheritable by future generations. Most studies suggest that around 0.8 percent of the U.S. and U.K. population is CIHHV6 positive, thus carrying a copy of HHV-6 in each cell. While most CIHHV-6 individuals appear healthy, they may be less able to defend themselves against other strains of HHV-6 that they might encounter. Some of these individuals suffer from a CFS-like illness. In a cohort of CFS patients with serious neurological symptoms, Shara and colleagues found that the prevalence of CIHHV-6 was over 2 percent, or more than twice the level found in the general public. In light of this finding, the studies suggest naming this sub-category of CFS “Inherited Human Herpesvirus 6 Syndrome,” or IHS; a novel disease.

Untreated CIHHV-6 patients with CFS showed signs that the HHV-6 virus was actively replicating: determined by the presence of HHV-6 messenger RNA (mRNA), a substance produced only when the virus is active. Importantly, HHV-6 mRNA disappeared by the sixth week of antiviral therapy with valganciclovir, a drug used to treat closely related cytomegalovirus (HHV-5). Of note, short-term treatment regimens, even up to three weeks, had little or no impact on the HHV-6 mRNA level. The investigators assumed that the integrated virus had become reactivated in these patients; however, to their surprise, they found that these IHS patients were infected by a second unrelated strain of HHV-6. The USF-led study was supported by the HHV-6 Foundation and the National Institutes of Health. Further studies are needed to confirm that immune dysregulation, along with subsequent chronic persistence of the HHV-6 virus, is the root cause of the IHS patients’ clinical symptoms, the research reports.

The good news reported in the study is that antiviral drugs improve the severe neurological symptoms, including chronic long-term fatigue suffered by a certain group of patients with CFS. An estimated 15,000 to 20,000 patients with this CFS-like disease in the United States alone may ultimately benefit from the application of this research including antiviral drug therapy.

Article citation: “Persistent human herpesvirus-6 infection in patients with an inherited form of the virus; ” Shara N. Pantry, Maria M. Medveczky, Jesse H. Arbuckle, Janos Luka,Jose G. Montoya, Jianhong Hu, Rolf Renne, Daniel Peterson, Joshua C. Pritchett, Dharam V. Ablashi, andPeter G. Medveczky; Journal of Medical Virology; published online July 25, 2013; DOI: 10.1002/jmv.23685

Science CodexJMV

Peter

Peter G. Medveczky, M.D. Professor
Department of Molecular Medicine
College of Medicine
University of South Florida
MDC Box 7
12901 Bruce B. Downs Blvd.
Tampa, FL 33612-4799

Phone; (813) 974-2372
Email; pmedvecz@health.usf.edu