November 20, 2009

Aliquots — research highlights from VUMC laboratories

Protein protector against DNA stress

Genome maintenance systems prevent and repair DNA damage to maintain the genome’s stability and protect against mutations that cause cancer and other diseases.

In their search for novel genome maintenance factors, David Cortez, Ph.D., and colleagues have identified SMARCAL1 as a genome maintenance protein. Mutations in SMARCAL1 are known to cause the rare genetic disorder Schimke immunoosseous dysplasia (SIOD), which is characterized by short stature, kidney disease and a weakened immune system. But the function of SMARCAL1 and its mechanistic role in the disease have remained unclear.

In the Oct. 15 issue of Genes & Development, the researchers describe the cellular functions of this protein. They found that SMARCAL1 protein acts to limit DNA damage at stalled replication “forks” (sections of unwound DNA undergoing replication). The findings suggest that mutations in SMARCAL that result in defective cellular responses to replication stress may at least partially explain the variety of symptoms associated with SIOD.

Melissa Marino


Shot of vitamin C for memory?

High levels of dietary vitamin C (ascorbate) have been linked to lower risk of developing Alzheimer’s disease. High-dose ascorbate treatment also improves learning and memory in some animal studies, but the responsible mechanisms are unclear.

Fiona Harrison, Ph.D., and colleagues are investigating the cognitive-enhancing effects of ascorbate injections (rather than oral treatments) in a mouse model of Alzheimer’s disease. In the October issue of Pharmacology, Biochemistry and Behavior, they report that a short series of acute ascorbate injections improved memory in both the Alzheimer’s mouse model and aged normal mice.

The treatments did not improve the neuropathological features seen in aging Alzheimer’s model mice, suggesting that the memory-enhancing actions of ascorbate may be due to an acute pharmacological mechanism modulating neurotransmitter function. In a follow-up study in the Dec. 28 Behavioural Brain Research, they demonstrate that ascorbate can block the amnesia-inducing effects of scopolamine, a drug that inhibits the action of the neurotransmitter acetylcholine.

The studies suggest that high-dose ascorbate, administered by injection, may offer short-term memory improvements by influencing acetylcholine neurotransmission in the brain.

Melissa Marino


Toxin vs. mutant toxin

Clostridium perfringens – a relative of the bacteria that cause botulism and tetanus – produces one of the most potent bacterial toxins. Its epsilon-toxin can be fatal to farm animals, and because the toxin may also affect humans, it is considered a “select agent” by the U.S. government. A vaccine and an antitoxin are available to protect livestock against epsilon-toxin, but neither is acceptable for human use.

In the Oct. 23 issue of the Journal of Biological Chemistry, Teal Pelish and Mark McClain, Ph.D., describe two “dominant-negative” epsilon-toxin inhibitors. These inhibitors are mutant forms of the epsilon-toxin that do not kill cells and that are able to block the activity of the wild-type toxin when the two proteins are mixed together. The two epsilon-toxin inhibitors block the ability of the active epsilon-toxin to assemble into pore-forming complexes in the cell membrane. These dominant-negative inhibitors provide the basis for developing new therapeutics directed against epsilon-toxin.

Leigh MacMillan


Getting gene priorities in order

Over the past decade, studies searching for the genes that cause complex diseases have generated a vast array of genetic data. But strategies for prioritizing candidate genes for follow-up studies have relied mostly on investigator intuition and have often limited follow-up to the “usual suspects” – genes with functions that “fit” the disease.

Zhongming Zhao, Ph.D., and colleagues have now developed a bioinformatics approach that integrates data from multiple sources to prioritize candidate genes for follow-up studies. In the Oct. 1 issue of the journal Bioinformatics, they demonstrate the approach in schizophrenia.

They collected all of the available genetic studies of schizophrenia, including more than 2000 association studies, genome-wide linkage scans and gene expression studies. They developed a weighting scheme to rank genes using data from different studies, evaluated the prioritized candidate genes using other independent data sets, and found them to be promising for further analysis. The gene prioritization approach, which can be applied to other complex diseases, is available at SZGR/.

Leigh MacMillan


We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to:

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012