November 26, 2010
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Ivermectin Nails Neurotransmission in Brugia malayi
Published in PNAS, November 16, 2010
Well over 100 million people are currently infected with Brugia malayi, a microscopic nematode that causes lymphatic filariasis. Infection can eventually lead to the chronic inflammatory disease known as elephantiasis. In an effort to better understand this parasitic creature Dr. Timothy Geary and his team in the Institute of Parasitology at McGill University took a closer look at its glutamate-gated chloride channels (GluCls). These channels are localized to a very specific muscle structure surrounding an excretory vesicle in B. malayi and are essential for controlling protein release. Researchers show that ivermectin, a broad-spectrum anti-parasitic medication commonly deployed to reduce B. malayi infection, directly interferes with GluCl function preventing excretion of proteins from this excretory site. As protein excretion is known to be a very important aspect of the parasites survival system, allowing it to evade the immune system of the host it colonizes, researchers attribute the effectiveness of ivermectin to its ability to interfere with neurotransmission at GluCls. Screening for additional compounds that interact with GuCls could provide new treatment paradigms for B. malayi infection in the future.
Prion Disease: A Sticky Situation
University of Toronto ♦ University of British Columbia
Published in PNAS, November 16, 2010
Prion diseases include the infamous mad-cow disease (bovine spongiform encephalopathy), fatal familial insomnia, and the human disease ‘kuru’. The latter of these, believe it or not, being caused by human cannibalism and documented in small tribes located in Papua New Guinea that partake in strange funeral rituals following the deaths of relatives (I’ll spare you the details). These neurodegenerative diseases are often terminal and are caused by proteins, known as a prions, that have a propensity to aggregate together forming dangerous plaques that ultimately destroy neural tissue. Not all prion proteins are bad however, their behaviour depends on structural state. A switch from the α-helical conformation to the pathological β-form leads to rogue prion proteins that ‘stick’ to one another. Researchers at the University of Toronto were curious as to why animals of different sizes have different susceptibilities to prion diseases. In this study led by Dr. Avijit Chakrabartty, scientists used X-ray crystallographic structure analysis and a rabbit model to identify cellular mechanisms that explain the rabbit’s relative immunity to prion diseases. A helix-capping motif found in rabbits prevents folding of prion proteins into the pathological state. Findings like these, elucidating the underlying mechanisms driving transformation to the pathological state, should help us brainstorm future therapies for these deadly diseases.
November 5, 2010
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A Deadly Competitor: The marine bacterium Vibrio cholerae has built-in mechanisms that may allow it to compete with other species of bacteria and better colonize its host. Researchers recently discovered a secretion system (T6SS) in V. cholerae allowing it to inject toxic substrates directly into the cytoplasm of prey. Now a group at the University of Alberta, led by Dr. Stefan Pukatzki, has shown that this strain of bacteria aggressively competes against a number of gram-negative bacteria including Escherichia coli and Salmonella and was able to reduce E. coli survival by 100,000-fold. It would be interesting to see whether the disruption of T6SS could be used as a tool to put a damper on cholera outbreaks and/or increase the time between outbreaks. Find the study published in PNAS.
Signature of Kidney Disease: The most common form of glomerular-based kidney disease is IgA nephropathy (IgAN). Roughly 40% of patients suffering from the disease will experience kidney failure in 10 years. The strongest predictor of clinical outcome in IgAN is proteinuria, or elevated levels of protein in the blood – often albumin. Researchers at the University of Toronto have identified what appears to be a genetic signature of the disease. An in vitro model of proteinuria was created by exposing primary human kidney tubular epithelial cells to high levels of albumin. Gene expression in these cells was then measured with a microarray to derive a panel of 231 “albumin-regulated genes” that were upregulated or repressed as a result of albumin exposure. Researchers then translated this to the clinic by analyzing biopsy samples from patients with IgAN. What they found is that they were able to perfectly segregate biopsy samples from control samples. Convincingly, the panel could be reduced to 11 genes and be used to distinguish any form of primary glomerulonephritis from control, suggesting that this signature could have great utility in predicting clinical outcome in glomerular-based kidney disease in the future. This study included researchers from the University of Toronto, University of Michigan, and University Hospital Zurich in Switzerland. Find it here in PLoS ONE.
Thyroid On the Move: The congenital endocrine disorder hypothyroidism results from improper differentiation, migration, or growth of thyroid tissue. In a majority of cases (~80%), incomplete migration leads to ectopic thyroid tissue. Previous studies with identical twins suggest that the disease is almost certainly caused by somatic mutations or epigenetics as in some cases there have been discordance rates of up to 92%. In a recent study published in PLoS ONE, scientists used microarray analysis to uncover 1011 genes that were either induced or repressed by a factor of 2-fold in ectopic thyroid nodules. Grouping of these genes into gene ontology groups using DAVID (Database for Annotation, Visualization, and Integrated Discovery) identified several clusters of genes related to development and organogenesis. After validating many of these genes, 19 were isolated as being exclusively related to thyroid ectopy. Genes involved in embyronic development (TXNIP) and the Wnt pathway were among those that contributed most to formation. Further work on a larger cohort of patients may allow for elucidation of the molecular mechanisms behind defective thyroid migration during early embryogenesis.