October 10, 2008

Aliquots — Research highlights from VUMC laboratories

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Sensing role for Alzheimer’s protein

Amyloid precursor protein (APP) lies at the heart of Alzheimer’s disease. The protein gets chopped up into various fragments, some of which accumulate and form “plaques” in the brain, and others that do not accumulate. Besides being the precursor of the plaque-forming proteins, APP has no clear function.

In the Sept. 9 issue of Biochemistry, Charles Sanders, Ph.D., and colleagues report the structure of a key APP domain, called C99, which reveals a possible function for APP. They found that cholesterol binds specifically to C99, suggesting that cholesterol may help traffic APP to cholesterol-rich areas of the cell membrane – sites at which APP is more likely to be cleaved into the plaque-forming fragments.

Because one of the APP-derived fragments can turn down the cell’s ability to take up cholesterol, the authors suggest that APP might act as a cellular “cholesterol sensor,” offering a possible new function for the enigmatic protein.

Melissa Marino


Genetic risks for being born early

Preterm birth – before 37 weeks of gestation – occurs in more than 10 percent of all pregnancies in the United States and is the largest contributor to infant morbidity and mortality.

To dissect genetic risk factors for preterm birth, Scott Williams, Ph.D., and colleagues performed a large-scale gene association study on a U.S. Caucasian population – a group with climbing preterm birth rates. The investigators analyzed maternal and fetal DNA from 172 preterm cases and 198 term controls. They examined 1,536 genetic variants in 130 candidate genes – genes with roles in pathways implicated in preterm birth. The team found significant associations between preterm birth and maternal genes in the complement-coagulation pathway, a pathway related to placental hemorrhage. The strongest effect in fetal DNA was observed in the inflammatory pathway.

The findings in the September PLoS ONE support roles for genes in both coagulation and inflammatory pathways and suggest mothers and infants may have different genetic risks for preterm birth.

Leigh MacMillan


Metal helps DNA unwind

DNA generally sits in the nucleus in a compact, tangled heap. But to be transcribed or copied, DNA must be free of tangles and knots. The enzyme topoisomerase IIa generates transient double-stranded breaks in the genetic material, allows the DNA to unwind to release any knots or kinks, and then reconnects the broken strands. This process is critical to normal cell-ular processes, and several anticancer drugs work by interfering with the enzyme’s DNA cleavage-rejoining function. To work properly, topoisomerase IIa requires a metal ion (usually magnesium), but the role of this metal has been unclear.

In the September Nucleic Acids Research, Neil Osheroff, Ph.D., and his student, Joseph Deweese, report that the DNA cleavage reaction of topoisomerase IIa actually requires two metal ions, one of which interacts with a key atom in the DNA, greatly accelerating the rate of DNA cleavage by the enzyme. Given the enzyme’s important role as a target of anticancer therapy, understanding how topoisomerase IIa cleaves DNA could provide new leads for developing chemotherapeutic agents.

Melissa Marino


A function-regulating partner for DAT

The neurotransmitter dopamine is a key player in brain circuits linked to attention, motor function, reward and cognition. Molecular “vacuum cleaners” known as dopamine transporters (DATs) regulate dopamine signaling by sucking the transmitter out of the space between neurons.

Louis DeFelice, Ph.D., and colleagues previously discovered that DATs also have a “channel mode” – they generate electrical currents that influence neuronal excitability. Now, the team reports that a protein called syntaxin 1A (Syn1A) associates with DAT and suppresses its channel properties in the worm, C. elegans. Disruption of the interaction between DAT and Syn1A altered normal worm behavior – rather than swimming, the worms were paralyzed, a behavior associated with excess dopamine release and consistent with increased DAT channel activity.

The findings in the Sept. 16 Proceedings of the National Academy of Sciences suggest that altered Syn1A-DAT interactions in humans could support dopamine-associated disorders, such as schizophrenia, addiction and attention deficit hyperactivity disorder.

Leigh MacMillan

Past Aliquots

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