January 23, 2009

Aliquots — Research highlights from VUMC laboratories

Featured Image

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: aliquots@vanderbilt.edu.


Genome scan finds dementia locus

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. Although genetic determinants are implicated in the development of late-onset AD, the most common form that develops after age 60, few genes have been definitively linked to the disease.

In an attempt to find genes that might increase an individual’s risk for late-onset AD, Jonathan Haines, Ph.D., Margaret Pericak-Vance, Ph.D., and colleagues performed a genome-wide association study (GWAS), scanning the entire genome (550,000 variations) of 492 people with late-onset AD and 498 controls.

They report in the January issue of the American Journal of Human Genetics the strong association of a variant on chromosome 12 with late-onset AD. The region is near the vitamin D receptor gene, an appealing candidate that has previously been linked to AD. Low vitamin D levels also have been reported in patients with AD and other dementias. The investigators also identified four other strongly associated regions and validated nine candidate genes that show association in their study and in another GWAS.

— Leigh MacMillan


Paralysis from protein back-up?

Hereditary spastic paraplegia (HSP) is a progressive degenerative disease of the spinal cord that impairs the ability to walk. Mutations in the gene NIPA1 have been associated with one form of HSP. To explore the cellular consequences of these mutations – which have remained unclear – Peter Hedera, M.D., and colleagues inserted the human NIPA1 mutations into various cell lines and into the worm C. elegans.

In the Dec. 17 Journal of Neuroscience, the researchers report that the subcellular distribution of mutant NIPA1 is dramatically altered compared to normal (wild-type) NIPA1. The mutant protein accumulates in the endoplasmic reticulum, the site of protein processing and transport, triggering cell death. Worms carrying mutant NIPA1 exhibited a progressive loss of motor neurons (beginning at day 7) and rapid impairment of motor function with complete paralysis by day 9. The neuronal degeneration due to toxic build-up of NIPA1 protein suggests that therapies aimed at reducing NIPA1 accumulation might help slow the progression of the disease.

— Melissa Marino


Of yeast and men: genome protectors

Genome “surveillance systems” prevent and repair DNA damage to maintain the genome’s stability and protect against cancer-causing mutations. One such system in human cells includes a pair of proteins, ATR and ATRIP. David Cortez, Ph.D., and colleagues previously identified a protein (TopBP1) that interacts with both ATR and ATRIP and stimulates their genome surveillance functions.

The yeast Saccharomyces cerevisiae, a popular model organism for genetics research, contains a version of human ATR-ATRIP, called Mec1-Ddc2. In the Dec. 2 Proceedings of the National Academy of Sciences, Cortez and colleagues identify a protein, called Dpb11, as the activator of Mec1 and the functional “cousin” to human TopBP11. Additionally, they found that Ddc2 interacts genetically and physically with Dpb11 – an interaction similar to that of the human versions of these proteins.

The results demonstrate that this genome surveillance system is conserved from yeast to humans – a finding that could facilitate the study of these cancer-protective mechanisms in a simple model organism.

— Melissa Marino


Cell surface target for cold virus

Human metapneumovirus (hMPV) – first identified in 2001 – is a major cause of serious respiratory illness in young children, but there are no licensed vaccines or antiviral therapies for it.

John Williams, M.D., and colleagues are studying how hMPV causes disease with the aim of finding ways to stop the virus. They have now identified a protein called integrin avb1 as the first functional receptor for hMPV.

The researchers show that antibodies that block avb1 reduce infection of cells by hMPV, but not by its close relative, respiratory syncytial virus. Reducing integrin subunit av or b1 expression also inhibited hMPV infection, while expressing the subunits in cells that hMPV cannot normally infect allowed infection. The team also demonstrated that purified hMPV fusion protein binds to cells, but not when its conserved integrin-binding motif is altered. The findings, reported in the Proceedings of the National Academy of Sciences, extend the role of integrins as receptors for viral pathogens and provide potential therapeutic targets for hMPV.

— 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