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'Deranged calcium signaling' contributes to neurological disorder, UT Southwestern researchers find
Date:11/26/2008

DALLAS Nov. 25, 2008 Defective calcium metabolism in nerve cells may play a major role in a fatal genetic neurological disorder that resembles Huntington's disease, researchers at UT Southwestern Medical Center have found in a mouse study.

The disease, called spinocerebellar ataxia 3 also known as SCA3, or Machado-Joseph disease is a genetic disorder that, like Huntington's, impairs coordination, speech, and vision and causes brain atrophy. Although rare, the condition is one of the most common inherited forms of ataxia and most frequently affects people of Portuguese descent.

The UT Southwestern researchers previously had found that calcium flow within nerve cells is disrupted in Huntington's disease. The latest findings, appearing in the Nov. 26 issue of the Journal of Neuroscience, suggest that SCA3, which is caused by a genetic defect similar to the one found in Huntington's, involves the same "deranged calcium signaling," researchers said.

Both SCA3 and Huntington's are caused by repeating segments of DNA, although the repeats associated with each disease appear in different genes that code for different proteins. The genetic mutations cause repeated units of the amino acid glutamine to appear in the respective proteins. The more repeats there are, the earlier the onset of the disease.

In Huntington's disease the mutated protein is Huntingtin; in SCA3 it is ataxin-3.

The researchers determined that the mutant human ataxin-3 activates a molecule that acts as a channel in the membrane of a sequestered chamber inside cells called the endoplasmic reticulum, or ER. The channel then releases calcium into the cell as a whole. Normal ataxin-3 did not activate the channel or cause calcium release.

The researchers also found that cells from a person with SCA3 showed abnormally high levels of calcium release when treated with bradykinin, a substance that also activates the calcium channel.<
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Contact: Aline McKenzie
aline.mckenzie@utsouthwestern.edu
214-648-3404
UT Southwestern Medical Center
Source:Eurekalert  

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