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More genes for Lou Gehrig's disease identified, according to Penn researchers
Date:4/7/2008

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 Gehrigs 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 wit
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert

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