Public Release:  New genes for risk and progression of rare brain disease identified

Initial step towards early identification and treatment of progressive supranuclear palsy

University of Pennsylvania School of Medicine

PHILADELPHIA - 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 ε3/ε4 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.

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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.

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