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Malfunctioning gene associated with Lou Gehrig's disease leads to nerve-cell death in mice
Date:1/5/2011

PHILADELPHIA Lou Gehrig's disease, or amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD) are characterized by protein clumps in brain and spinal-cord cells that include an RNA-binding protein called TDP-43. This protein is the major building block of the lesions formed by these clumps.

In a study published in the Journal of Clinical Investigation, a team led by Virginia M.-Y. Lee, PhD, director of Penn's Center for Neurodegenerative Disease Research, describes the first direct evidence of how mutated TDP-43 can cause neurons to die. Although normally found in the nucleus where it regulates gene expression, TDP-43 was first discovered in 2006 to be the major disease protein in ALS and FTLD by the Penn team led by Lee and John Q. Trojanowski, MD, PhD, director of the Institute on Aging at Penn. This discovery has transformed research on ALS and FTLD by linking them to the same disease protein.

"The discovery of TDP-43 as the pathological link between mechanisms of nervous system degeneration in both ALS and FTLD opened up new opportunities for drug discovery as well as biomarker development for these disorders," says Lee. "An animal model of TDP-43-mediated disease similar to ALS and FTLD will accelerate these efforts."

In the case of TDP-43, neurons could die for two reasons: One, the clumps themselves are toxic to neurons or, two, when TDP-43 is bound up in clumps outside the nucleus, it depletes the cell of normally functioning TDP-43. Normally a cell regulates the exact amount of TDP-43 in itself -- too much is bad and too little is also bad. The loss of function of TDP-43 is important in regulating disease because it regulates gene expression.

To determine the effects of misplaced TDP-43 on the viability of neurons, the researchers made transgenic mice expressing human mutated TDP-43 in the cytoplasm and compared them to mice expressing normal human TDP-43 in the nucleus of nerve
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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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Malfunctioning gene associated with Lou Gehrig's disease leads to nerve-cell death in mice
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