Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New genes for risk and progression of rare brain disease identified

20.06.2011
Initial step towards early identification and treatment of progressive supranuclear palsy

There are new genetic clues on risk factors and biological causes of a rare neurodegenerative disease called progressive supranuclear palsy (PSP), according to a new study from an international genetics team led by researchers from the Perelman School of Medicine at the University of Pennsylvania.

In the largest genetics study of the disease, three new genes associated with risk for PSP were identified and two additional genetic variants affecting risk for PSP were confirmed. The paper appears in online in Nature Genetics.

This gives new insight into a disease that has intriguing contrasts and similarities to other neurodegenerative diseases, including Parkinson's disease, frontotemporal dementia (FTD) and Alzheimer's disease.

"PSP is a devastating disease with no available treatments. This work increases what we know not only about the genetics but also about the underlying cause of the disease," said Gerard Schellenberg, PhD, professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania and the study's senior author. "We hope this work not only will benefit patients with PSP, but will also increase our understanding of related more common diseases, such as Alzheimer's disease."

Progressive supranuclear palsy (PSP), a form of frontotemporal dementia, affects around 3-6 people per 100,000 and, after Parkinson's disease, is the second most common cause of degenerative parkinsonism. The disease is characterized by a difficulty coordinating eye movement, imbalance and gait instability, stiff movements, mood and emotional changes. Biologically, PSP is primarily caused by an abnormal accumulation of tau protein, which is well-known for its secondary role in Alzheimer's disease. Both environmental insults (i.e. repetitive brain trauma) and inherited factors contribute to the risk of developing tauopathies.

In a genome wide association (GWA) study comparing 1,114 autopsy-confirmed cases of PSP to 3,287 control subjects, researchers found significant genetic variations in three regions, at EIF2AK3, STX6 and MOBP. The study was replicated with a second set of subjects (1,051 clinically diagnosed with PSP, compared to 3,560 unique controls).

Three newly-identified genes include:

EIF2AK3 is a gene that encodes for endoplasmic reticulum unfolded protein response (UPR) which clears potentially toxic misfolded proteins. UPR disruption can influence PSP risk, according to researchers, and modifying the UPR has the potential to modify risk and possibly the course of disease.

STX6 encodes a protein called syntaxin 6 (Stx6) that typically shuttles vesicles within the cell, but genetic variation at STX6 may change intracellular transport or cause toxin absorption, contributing to PSP disease development.

The function of MOBP and the protein it encodes, MOBP, is still unclear, but the protein is found in brain regions affected in PSP and may be involved in myelin formation.

MAPT Gene Variations Show Risk

Previous work showed that genetic causes of tauopathies include mutations in the gene that encodes microtubule associated protein tau (MAPT). In this study, researchers confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The risk associated with the more common MAPT H1 haplotype was statistically stronger than the effect the APOE å3/å4 genotype has on Alzheimer's disease risk (95 percent of PSP subject chromosomes had the H1 polymorphism, compared to 77.5 percent of controls).

There is no current genetic test to measure PSP risk, but these findings are the first step in understanding the genes associated with risk for PSP, which could someday lead to the ability to predict more accurately who will get this disease. "Prediction will become important when we have preventative therapies for this devastating condition," said Dr. Schellenberg.

Researchers now have another drug discovery target to investigate – a drug to modulate the unfolded protein response to modify the risk and progression of PSP.

With no FDA-approved treatment to change the course of this rare disease, clinical trials and drug discovery efforts looking for potential PSP treatments are greatly needed. A Phase 2/3, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of Allon's davunetide is looking to treat the underlying pathology of PSP while also improving symptoms of the disease. The davunetide trial is currently enrolling PSP patients at Penn Medicine, interested patients are encouraged to visit ClinicalTrials.gov and talk to their physician to determine eligibility.

The genetics study was conducted by an international team of more than 135 researchers, including the PSP Genetics Study Group. In addition to Dr. Schellenberg, the team from Penn Medicine includes Li-San Wang, PhD, Howard Hurtig, MD, Rachel Goldman Gross, MD, Steven Arnold, MD, Murray Grossman, MD, Virginia M-Y Lee, PhD, MBA, and John Trojanowski, MD, PhD.

The work was funded by grants from organizations including the Cure PSP Foundation, the Peebler PSP Research Foundation and the National Institutes of Health (NIH)'s National Institute on Aging (NIA) and National Institute of Mental Health (NIMH).

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.

Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit our community.

Kim Menard | EurekAlert!
Further information:
http://www.upenn.edu

More articles from Life Sciences:

nachricht At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History

nachricht New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

Im Focus: Autonomous 3D scanner supports individual manufacturing processes

Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).

Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Fingerprints of quantum entanglement

16.02.2018 | Information Technology

'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers

16.02.2018 | Health and Medicine

Hubble sees Neptune's mysterious shrinking storm

16.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>