November 7, 2008

Aliquots — Research highlights from VUMC laboratories

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One drug for two cognitive disorders?

Muscarinic acetylcholine receptors (mAChRs) modulate many central nervous system functions, including cognition and motor control. The M1-type receptor has been pursued as a therapeutic target for improving cognitive function in patients with Alzheimer’s disease as well as schizophrenia. However, drugs developed to activate this receptor – called muscarinic agonists – cause adverse side effects due to their activation of other types of mAChRs in addition to the M1 receptor, limiting their therapeutic potential.

By targeting “allosteric” sites on the receptor away from the site at which acetylcholine binds, Jeffrey Conn, Ph.D., and colleagues have developed a highly selective M1 agonist, called TBPB. The researchers found that TBPB reduced the accumulation of amyloid – a hallmark feature of Alzheimer’s disease – in cultured neurons. Additionally, TBPB alleviated psychosis-like symptoms in rats.

The results, appearing in the Oct. 8 issue of The Journal of Neuroscience, suggest that selective activation of M1 receptors may provide a novel approach to treating symptoms of Alzheimer’s disease and schizophrenia.

Melissa Marino


Golgi doesn’t stack up in bone disease

More than 200 clinically distinct diseases, including various forms of dwarfism, result from inherited defects in bone formation, or osteochondrodysplasias. Mutations in the dymeclin (Dym) gene cause two such disorders – Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia. However, the normal functions of dymeclin have not been determined.

To study the gene’s biological role, Anna Osipovich, Ph.D., and colleagues generated mice with a mutation in Dym. The mutant mice displayed defects in bone formation similar to those seen in these inherited syndromes – including shortened trunk and limbs, spine curvature, small skull, and reduced rib cage volume. Cultured cells with the mutation showed defects in protein trafficking and disorganization of the Golgi complex – an organelle composed of membrane-bound compartments involved in protein processing and transport.

The results, published in the Oct. 21 Proceedings of the National Academy of Sciences, suggest that dymeclin plays a role in protein and vesicle traffic to and from the Golgi, providing a potential molecular basis for osteochondrodysplasias in mice and humans.

Melissa Marino


Thinking about what’s in your genes

Mutations in the BMPR2 gene predispose an individual to developing pulmonary arterial hypertension (PAH), a rare and often fatal disease. About 20 percent of individuals with a mutation will develop PAH. Clinical genetic testing is available for BMPR2 mutations, but little is known about how patients with PAH and those at risk for the disease – because of a family history – think about the testing.

Ellen Clayton, M.D., J.D., and colleagues conducted telephone interviews of 119 individuals affected by or at risk for PAH. The majority of respondents felt that they knew little or nothing about BMPR2 testing, even though most said they had known about the test for at least a year. Despite their perceived lack of knowledge, most respondents expressed a willingness to be tested, to provide information for their children. The findings in the October Journal of Genetic Counseling suggest that counselors need to be proactive to assure that patients understand the clinical implications of testing for mutations in BMPR2.

Leigh MacMillan


Drug upsets heart’s post-surgery beat

Atrial fibrillation (AF) – an abnormal heart rhythm – is the most common complication after cardiac surgery, resulting in illness and longer hospital stays. Drugs that increase the contractile force of the heart, such as milrinone, are often used during surgery to support cardiac function. But the effect of these drugs on postoperative AF has not been well studied.

Mias Pretorius, M.B., Ch.B., Nancy Brown, M.D., and colleagues evaluated risk factors for AF in 232 patients who underwent elective cardiac surgery. Nearly 30 percent of the patients developed AF about three days after surgery. They report in the Oct. 14 issue of Circulation that milrinone use during surgery increased the risk of postoperative AF 2- to 4-fold, even after accounting for other risk factors such as age, heart function and pulmonary artery pressure. The findings suggest that milrinone use during surgery could cause more than 56,000 cases of postoperative AF per year in the United States, with clear clinical and financial implications.

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