Newsroom News Archive Publications Contact Us for Experts
Media Contacts
Karen Kreeger
(215) 349-5658

Related Links
Perelman School of Medicine
University of Pennsylvania Health System

Recommend Story
 
> Epigenetics Shapes Fate of Brain vs. Brawn Castes in Carpenter Ants
> Molecular Master Switch for Pancreatic Cancer Identified, Potential Predictor of Treatment Outcome
> Eat to Dream: Penn Study Shows Dietary Nutrients Associated with Certain Sleep Patterns
  All News Releases
 
    Media Resources
 
spacerNEWS RELEASE spacer Print Version
APRIL 7, 2008
 

More Genes for Lou Gehrig’s Disease Identified, According to Penn Researchers

   

PHILADELPHIA –In recent months a spate of mutations have been found in a disease protein called TDP-43 that is implicated in two neurodegenerative disorders: amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, and certain types of frontotemporal dementia (FTD). These mutations could potentially become candidates for drug targets.

Recently, colleagues at the University of Pennsylvania School of Medicine and Veterans Affairs in Seattle, WA have found two more mutations. They published their findings online in advance of print publication in the May issue of The Lancet Neurology.

“Now we have a direct link between the genetics and the clinical pathology of these diseases,” says co-author Vivianna M. Van Deerlin, MD, PhD, Assistant Professor of Pathology and Laboratory Medicine at Penn. “This solves the question of whether TDP-43 is involved in the disease itself or a just a byproduct of it.”

“Put this all together and it becomes completely convincing that there are mutations in this gene that causes some forms of ALS,” says co-author Gerard D. Schellenberg, PhD, Associate Director for Research, Veterans Affairs Puget Sound Health Care System, in Seattle, WA

Essentially, these mutations are hard evidence that TDP-43 is critical for the disease process. In some cases the accumulation of TDP-43 may initiate disease; in others, it might be a downstream player in the onset of pathology.

In late 2006, Virginia Lee, PhD and John Trojanowski, MD, PhD at the Center for Neurodegenerative Disease Research at Penn found that TDP-43 accumulated abnormally in post-mortem brain tissue from individuals diagnosed with either disease. The misfolded, disease protein was recovered from only affected central nervous system regions, which include the hippocampus, neocortex, and spinal cord. TDP-43 is normally involved in RNA and DNA processing, among other cellular tasks.

The research team surveyed 259 individuals with either ALS or ALS combined with FTD and brains with pathological TDP-43 protein present and determined the DNA sequence of the gene for TDP-43 and compared it to the normal TDP-43 sequence in people without these diseases.

“By doing this, we found two families in which a mutation was present and showed that the mutated gene tracked with the disease,” says Van Deerlin. “Within the same family, all people tested who have the disease carry the mutated form of TDP-43 and it was absent in the unaffected people tested.”

With this, the research group then asked: Do we see this same change in people that don’t have the disease outside of the families as controls? The group tested 747 Caucasian and 380 Chinese elderly people without the disease and didn’t find the mutated form of TDP-43 in any of them.

“What makes our paper completely distinctive is that we have post-mortem brain tissue from some individuals in one of the ALS families,” says Schellenberg. “We showed that people with a mutated form of TDP-43 actually have TDP-43 deposited in their brain.”

The researchers stress the implications beyond ALS and FTD: TDP-43 shows up in a variety of diseases, for example 20 percent of Alzheimer’s cases. “These findings are not just important to ALS, it’s every disease where there is a pathological form of TDP-43,” notes Schellenberg.  The next step will be to gain a better understanding of how the mutation in TDP-43 causes disease.

This work was funded by the National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), the Department of Veterans Affairs, the Friedrich-Baur Stiftung (0017/2007), the US Public Health Service, the ALS Association, and a fellowship from Fundació 'la Caixa', Spain.

###

PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

 



About Penn Medicine   Contact Us   Site Map   Privacy Statement   Legal Disclaimer   Terms of Use

Penn Medicine, Philadelphia, PA 800-789-PENN © 2013, The Trustees of the University of Pennsylvania