Rodal lab find surprising new link between inflammation and Lowe Syndrome

Could a disease with symptoms in the brain, eyes, and kidneys actually be caused by problems with immune cells? A team of scientists from the Rodal Lab, co-first authored by Steven Del Signore and Sarah Biber and including three Brandeis undergraduates (Katy Lehmann ‘16, Stephanie Heimler ‘17, and Ben Rosenfeld ’18), think this just might be the case with Lowe Syndrome, in a new paper published Oct 13th in PLOS Genetics.

Patients with Lowe Syndrome suffer from kidney failure, congenital cataracts, and several neurological problems including intellectual disability and seizures. Scientists have known for some time that the disease is caused by mutations in a gene called OCRL, but remain unsure how its loss causes such a diverse array of symptoms. A big problem has been that OCRL appears to do many different jobs inside cells, including controlling how they divide, how they sense their surroundings, and how they store and transport materials inside small packages called endosomes.

Fly immune cells showing the tracks of moving endosomes. Single tracks represent the path of individual endosomes over time.

To try to solve this mystery, a team of researchers from the Rodal lab used the fruit fly, which has its own version of the OCRL gene and allowed the investigators to perform powerful genetic experiments to figure out precisely what OCRL is doing, and where. To do this, the group created a fly missing its OCRL gene. They were surprised to find that, rather than eye or neurological defects, loss of OCRL hyper-activated cells of the innate immune system. The innate immune system is the first line of defense against infection in humans (and the only defense in fruit flies), when cells release inflammatory signals that mobilize specialized cells to attack invading pathogens.

The team determined that OCRL is required in one of these specialized immune cells in the fly, and that the immune-cell activation was caused by problems in a particular step of intracellular transport. Every cell of the body has its own postal service, which is used to pack and ship signals that tell the cell or its neighbors to grow, divide, or jump into action (see movie here to watch endosomes moving inside living fly immune cells). The OCRL mutant immune cells had a problem in a key step that controls whether signals get thrown in the trash or shipped outside the cell, and this caused the immune activation.

How do these findings relate to Lowe Syndrome? The authors think these results suggest a possible cause for the seizures that patients experience. When similar immune-like cells in the brain release excessive inflammatory signals, it can cause several forms of epilepsy. Further, OCRL has been linked to at least one mouse model of epilepsy. Going forward, the researchers will try to identify which immune signals are responsible, and how these findings translate to human cells.

Del Signore SJ (*), Biber SA (*), Lehmann KS, Heimler SR, Rosenfeld BH, Eskin TL, Sweeney ST, Rodal AA. dOCRL maintains immune cell quiescence by regulating endosomal traffic. Plos Genet. 2017;13(10):e1007052.

 

 

Ivanovic Receives 2017 NIH Director’s New Innovator Award

photo: Mike Lovett

Assistant Professor of Biochemistry Tijana Ivanovic has received a 2017 NIH Director’s New Innovator Award. This award is part of the NIH’s High-Risk, High-Reward Research program, designed to fund early career investigators who propose innovative and potentially transformative projects. Ivanovic will receive $1,500,000 in direct costs over five years to spearhead a research program aimed at comprehensively characterizing molecular changes in the viral cell-entry protein hemagglutinin (HA) that define pandemic influenza viruses. With the generated insights, Ivanovic hopes to ultimately be in a position to predict the pandemic potential of influenza viruses circulating in nature.

HA densely covers the influenza virion surface, where it allows the virus to both recognize and penetrate (fuse with) the cells of its host. HA is also a key target of neutralizing antibodies that protect us from influenza infection. An influenza pandemic is characterized by the adaptation of a new HA subtype to cell entry into human cells (of what was originally an avian virus). Without the pre-existing immunity to protect us, the virus quickly spreads around the globe. During pandemic adaptation, both HA functions in target-cell recognition and membrane fusion undergo key molecular changes. Ivanovic will use a custom-built Total Internal Reflection Fluorescence Microscope (TIRFM) to visualize, in real time, individual virus particles as they engage and fuse with target cell membranes. This system will allow her to obtain large-scale quantitative information about distinct HA functions at an unprecedented level of detail. She will compare avian viruses with their evolutionary offspring that infected humans, including past pandemic strains. She hopes to develop models for predicting which viruses will lead to a major flu outbreak.

Ivanovic obtained a PhD in virology from Harvard University and carried out postdoctoral research with Stephen Harrison in molecular biophysics. She integrates these diverse backgrounds in her laboratory, where members are trained across these two and other synergistic areas (such as laser microscope optics, and analytical and computational modeling). The funds from the New Innovator award have created new opportunities for hiring, and the lab is actively recruiting postdocs, PhD students (from the Biochemistry and Biophysics, Molecular and Cell Biology, and Physics graduate programs) and undergraduate researchers to undertake this ambitious program.

Titia de Lange to receive 47th Rosenstiel Award

Professor Titia de Lange

The 47th Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research has been awarded to Professor Titia de Lange of Rockefeller University for her studies on the protection of chromosome ends (telomeres) from degradation and rearrangement. Professor de Lange will receive the award on April 12, 2018 at Brandeis University where de Lange will present a public lecture.

Dr. de Lange’s laboratory identified and characterized the roles of proteins that compose the shelterin complex, which binds specifically to the special telomeric DNA sequences and maintains the stability of these ends.  Dr. de Lange’s work has shown that the shelterin complex and the unusual telomere-loop structure of telomere DNA prevent these ends from being detected as broken chromosome ends and thus protect telomeres from being degraded and rearranged as are the ends at chromosome breaks.  De Lange’s work has further shown that disabling different components of shelterin triggers different cellular alarms designed to detect broken and degraded DNA ends and leads to lethal chromosome rearrangements such as the fusion of chromosomes.  In addition, her lab has gained critical insights into the mechanisms of cellular response to the presence of DNA damage and recently has defined processes that lead to massive chromosome rearrangements (chromothripsis) associated with many human cancers.

She is the Leon Hess Professor and director of the Anderson Center for Cancer Research at Rockefeller University, as well as an American Cancer Society Research Professor.  Her honors include: the Life Sciences Breakthrough Prize, the Rosalind E. Franklin Award from the National Cancer Institute, the Vilcek Prize in Biomedical Sciences, election as a foreign member of the US National Academy of Sciences and as Fellow of the American Academy of Arts and Sciences.

The Rosenstiel Award has had a distinguished record of identifying and honoring pioneering scientists who subsequently have been honored with the Lasker and Nobel Prizes.  Professor de Lange joins a long list of past awardees.

Garrity lab finds moisture-sensing genes in mosquitoes

Summary figure for Garrity lab paperby Zachary Knecht, PhD candidate

As the solvent of living cells, water is critical for all life on earth.  This makes monitoring how environmental conditions impact evaporation and subsequently sensing and locating water sources important for animal survival. This is particularly critical for insects, whose small body size makes them highly susceptible to dehydration. In addition, moisture sensing, or hygrosensation, is also important for the spread of insect-born disease. Mosquitoes that spread malaria or viruses like dengue and Zika, not only need to locate bodies of standing water in which to lay eggs, but also home in on the moisture that emanates from our bodies when searching for a blood meal. This dual role for hygrosensing in mosquito biology makes their hygrosensory machinery a promising target for pest control strategies. Until now though, the genes and molecules that function in insect hygrosensation have been completely unknown.

In a pair of recent papers in the journal eLife, researchers in the Garrity Lab at Brandeis University, in collaboration with colleagues at the University of Lausanne in Switzerland, have uncovered the cellular and molecular mechanisms that underlie insect hygrosensation using the fruit fly Drosophila melanogaster. Like mosquitoes, fruit flies detect humidity through specialized, innervated hair-like structures located on their antennae called sensilla. Each hygrosensing sensilla contains one cell that responds to increasing humidity (a moist cell), and one that responds to decreasing humidity (a dry cell).  These papers demonstrate that the balance of activity between dry and moist cells allows the insect to seek out or avoid particular humidity levels, a preference which changes depending on how hydrated or dehydrated the fly is.

To identify the molecules involved in sensing moisture, the researchers looked for mutant flies unable to distinguish between humid and dry air. They found that animals with mutations in four different genes disrupted the behavior. Strikingly, each of these genes encoded a different member of the same family of sensory receptors, the so-called Ionotropic Receptors or IRs.  Although IRs are found only in invertebrates, they belong to the same family as the ionotropic Glutamate Receptors, which lie at the heart of communication between nerve cells in the animal brain, including the human brain.  IRs differ from these relatives in that instead of sensing signals sent by neurons, they detect signals coming from the environment.  IRs are best known to act as chemical receptors, but the group found that a subset of IRs act instead to sense humidity. The researchers found two broadly expressed IRs, Ir25a and Ir93a, were required by both the dry cells and moist cells while the other two IRs, Ir40a and Ir68a, were specifically required by the dry and the moist cells, respectively. This suggests that Ir25a and Ir93a contribute to the formation of both moist and dry receptors, while Ir40a and Ir68a provide the dry- and moist-specific subunits to the receptor. Consistent with this view, the loss of either Ir68a or Ir40a alone only partially reduces the animal’s ability to sense humidity, but animals with mutations in Ir25a, Ir93a or both Ir40a and Ir68a are completely blind to moisture.

Having identified the specific genes required for sensing moisture, the next step is to determine the precise mechanism by which humidity activates these receptors. Furthermore, these genes are conserved in mosquitoes and other disease vectors, providing a clear path to translate what’s known about fly hygrosensation into the mosquito. These papers lay the groundwork for new mosquito control strategies that aim to precisely inhibit their ability to seek out water to reproduce and to seek out hosts to bite and spread deadly pathogens.

Leslie Griffith Receives SASTRA-Obaid Siddiqi Award

SASTRA award


Model depicts how the integration of light, ambient temperature, the circadian clock and homeostatic sleep drive sets the balance between daytime and nighttime sleep [Parisky, K.M., Agosto Rivera, J.L., Donelson, N.C., Kotecha, S. and Griffith, L.C. (2016) “Reorganization of sleep by temperature in Drosophila requires light, the homeostat and the circadian clock” Curr Biol 26:882-892]

Leslie C. Griffith, Nancy Lurie Marks Professor of Neuroscience and Director of the Volen National Center for Complex Systems, has received the SASTRA–Obaid Siddiqi Award for excellence in life sciences. The prize is given by the Shanmugha Arts, Science, Technology & Research Academy (SASTRA) University in Thanjavur, India. Siddiqi was a pioneering molecular biologist and founder of the Molecular Biology Unit of the Tata Institute for Fundamental Research.

Griffith’s interests range from the biochemistry of neuronal signal transduction, in particular the role of CaMKII in memory formation, to the hierarchical relationships between complex behaviors such as sleep and learning. She has contributed to our understanding of these issues using genetic approaches in Drosophila melanogaster and believes that model systems have an important place in pioneering the understanding of basic biological processes. Her lab has been active in developing tools that allow interrogation of molecular and cellular processes with temporal and spatial resolution in freely behaving animals to bridge the molecule-behavior gap.

Griffith received the award on February 28, 2017.

Dynamics of GreB-RNA polymerase interaction

Larry Tetone, Larry Friedman, and Melissa Osborne, and collaborators from the Gelles lab (Brandeis University) and the Landick lab (University of Wisconsin-Madison) used multi-wavelength single-molecule fluorescence methods to for the first time directly observe the dynamic binding and dissociation of an accessory protein with an RNAP during active transcript elongation.

Their findings are detailed in the recent paper “Dynamics of GreB-RNA polymerase interaction.” (PNAS, published online 1/30/2017).

Read more at The Little Engine Shop blog

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