The Benefits of Middle Age

Almost all our cells harbor a sensory organelle called the primary cilium, homologous to the better known flagella found in protists. Some of these cilia can beat and allow the cell to move (eg. in sperm), or move fluid (eg. cerebrospinal fluid) around them. However, other specialized cilia such as those found in photoreceptor cells and in our olfactory neurons function solely as sensory organelles, providing the primary site for signal reception and transduction. The vast majority of our somatic cells display a short and simple rod-like cilium that plays crucial roles during development and in adulthood. For instance, during development, they are essential for transducing critical secreted developmental signals such as Sonic hedgehog that is required for the elaboration of cell types in almost every tissue (eg. in brain, bones, muscles, skin). In adults, cilia are required for normal functioning of our kidneys, and primary cilia in hypothalamic neurons have been shown to regulate hunger and satiety.

Given their importance, it is not surprising that defects in cilia structure and function lead to a whole host of diseases ranging from severe developmental disorders and embryonic lethality to hydrocephalus (fluid accumulation in the brain), infertility, obesity, blindness, and polycystic kidney among others. Often these diseases manifest early in development resulting in prenatal death or severe disability, but milder ciliary dysfunction leads to disease phenotypes later in life.

Much is now known about how cilia are formed and how they function during development. However, surprisingly, how aging affects cilia, and possibly the severity of cilia-related diseases, is not well studied. A new study by postdocs Astrid Cornils and Ashish Maurya, and graduate student Lauren Tereshko from Piali Sengupta’s laboratory, and collaborators at University College Dublin and University of Iowa, begins to address this question using the microscopic roundworm C. elegans (pictured below). These worms display cilia on a set of sensory neurons; these cilia are built by mechanisms that are similar to those in other animals including in humans. Worms have a life span of about 2-3 weeks, thereby making the study of how aging affects cilia function quite feasible.

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They find that cilia structure is somewhat altered in extreme old age in control animals. However, unexpectedly, when they looked at animals carrying mutations that lead to human ciliary diseases, the severely defective cilia seen in larvae and young adults displayed a partial but significant recovery during middle-age, a period associated with declining reproductive function. They went on to show that the heat-shock response and the ubiquitin-proteasome system, two major pathways required for alleviating protein misfolding stress in aging and neurodegenerative diseases, are essential for this age-dependent cilia recovery in mutant animals. This restoration of cilia function is transient; cilia structure becomes defective again in extreme old age. These results suggest that increased function of protein quality control mechanisms during middle age can transiently suppress the effects of some mutations in cilia genes, and raise the possibility that these findings may help guide the design of therapeutic strategies to target specific ciliary diseases. Some things can improve with aging!

Irving Epstein has been named AAAS Fellow

irving-epstein

In recognition of his contribution to the study of oscillating chemical reactions, Irving Epstein, the Henry F. Fischbach Professor of Chemistry, has been selected as a Fellow in the American Association for the Advancement of Science (AAAS).

Epstein, who in his 45 years at Brandeis has served as Provost and Dean of the Arts and Sciences, said he was honored to receive the award from the AAAS. “I’m delighted and grateful for the recognition,” he said. “It’s always nice to be appreciated by fellow scientists.”

 

Amy Lee Joins Biology Faculty

On August 1, Amy Lee joined the Biology department as an Assistant Professor. Previously, Amy was an American Cancer Society Postdoctoral Scholar in Jamie Cate’s lab at University of California, Berkeley. She received her Ph.D. in Virology from Harvard University in Sean Whelan’s lab and her Bachelors of Science in Biology from Massachusetts Institute of Technology.

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eIF3d structure, see Figure 2 at http://rdcu.be/jzDD

Amy’s research focuses on understanding how gene regulation shapes cell growth and differentiation, and how dysregulation leads to human diseases like carcinogenesis and neurodegeneration. She is interested in discovering new mechanisms of mRNA translation initiation and novel functions of RNA-binding proteins and eukaryotic translation factors. Her research combines genome-wide and computational approaches together with molecular genetics, cell biology, biochemistry, and structural biology techniques.

Amy recently published a paper in Nature together with the Jamie Cate, Jennifer Doudna, and Philip Kranzusch describing the discovery of a new translation pathway that controls the production of proteins critical to regulating the growth and proliferation of cells. Cancer is characterized by uncontrolled cell growth, which means the protein production machinery goes into overdrive to provide the building materials and control systems for new cells. Hence, biologists for decades have studied the proteins that control how genes are transcribed into mRNA and how the mRNA is read and translated into a functioning protein. One key insight more than 40 years ago was that a so-called initiation protein must bind to a chemical handle on the end of each mRNA to start it through the protein manufacturing plant, the ribosome. Until now, this initiation protein was thought to be eIF4E (eukaryotic initiation factor 4E) for all mRNAs.

Amy and her colleagues discovered that for a certain specialized subset of mRNAs – most of which have been linked somehow to cancer – initiation is triggered by a different protein, called eIF3d. The finding was a surprise because the protein is part of an assembly of 13 proteins called eIF3 -eukaryotic initiation factor 3 – that has been known and studied for nearly 50 years, and no one suspected its undercover role in the cell. This may be because eIF3’s ability to selectively control mRNA translation is turned on only when it binds to the set of specialized mRNAs. Binding between eIF3 and these mRNAs opens up a pocket in eIF3d that then latches onto the end-cap of mRNA to trigger the translation process. Subsequent X-ray crystallography of eIF3d revealed the structural rearrangements that must occur when eIF3 binds to the mRNA tag and which open up the cap-binding pocket. eIF3d thus presents a promising new drug target in cancer, as a drug blocking this binding protein could shut off translation of only the growth-promoting proteins and not other life-critical proteins inside the cell.

Lee AS, Kranzusch PJ, Doudna JA, Cate JH. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature. 2016.

 

Using computer simulations to model bacterial microcompartment assembly

Bacterial microcompartments are protein shells found in bacteria that surround enzymes and other chemicals required for certain biological reactions.  For example, the carboxysome is a type of microcompartment that enables bacteria to convert the products of photosynthesis into sugars (thus taking carbon out of the atmosphere).  During the formation of a microcompartment, the outer protein shell assembles around hundreds of enzymes and chemicals required for the reaction.  Because the intermediates in this assembly process are small and short-lived, it is hard to study in detail using experiments. It is therefore useful to develop computational models that can help explain how proteins collect the necessary cargo, and then assemble into an ordered shell with the cargo on the inside.  The videos in this post show some examples of computer simulations of a model for bacterial microcompartment assembly, with each video corresponding to a different set of parameters that control the strengths of interactions among the proteins and cargo.

The study is described in the research article “Many-molecule encapsulation by an icosahedral shell” by Jason Perlmutter, Farzaneh Mohajerani, and Michael Hagan in eLife (eLife 2016;10.7554/eLife.14078).

Video 1: Multistep assembly of a microcompartment encapsulating hundreds of molecules (I) video1
Video 2: Multistep assembly of a microcompartment encapsulating hundreds of molecules (II)  video2
Video 3: Assembly of a microcompartment and encapsulation of hundreds of diffuse cargo molecules  video3

7th Annual Jay Pepose Award to be presented April 12 at 12:30 pm

David WilliamsDavid Williams from the University of Rochester has been selected to receive the 7th annual Jay Pepose ’75 Award in Vision Sciences. Williams will be presented with the Pepose award on Tuesday, April 12th at 12:30 pm in Gerstenzang 121. The celebration will include David Williams talk titled, “Seeing Through the Retina”.

Williams’ research has improved the effectiveness of laser refractive surgery, the design of contact lenses, and enabled the imaging of single cells in the retina.

Yoshinori Ohsumi to Receive Rosenstiel Award Wednesday, April 6

ohsumi220Biologist Yoshinori Ohsumi will receive the 45th Rosenstiel Award for Distinguished Work in Biomedical Science this Wednesday, April 6th at 4:00 pm in Gerstenzang 123. At that time, he will present a lecture titled, “Lessons from yeast: Cellular recycling system, autophagy”.

Ohsumi is a cell biologist and professor at the Tokyo Institute of Technology’s Frontier Research Center in Japan. He is one of leading experts in the world on autophagy, a process that allows for the degradation and recycling of cellular components. The Rosenstiel Award is being given to Ohsumi in recognition of his pioneering discoveries in autophagy.

Learn more about Professor Ohsumi and his research at BrandeisNow.

Fruit flies alter their sleep to beat the heat

Do you have trouble sleeping at night in the summer when it is really hot?

Does a warm sunny day make you want to take a nap?

You are not alone — fruit flies also experience changes in their sleep patterns when ambient temperature is high. In a new paper in Current Biology, research scientist Katherine Parisky and her co-workers from the Griffith lab show that hot temperatures cause animals to sleep more during the day and less at night, and then investigate the mechanisms governing the behavior.

The increase in daytime sleep is caused by a complex interplay between light and the circadian clock. The balance between daytime gains and nighttime losses at high temperatures is also influenced by homeostatic processes that work to keep total daily sleep amounts constant. This study shows how the nervous system deals with changes caused by environmental conditions to maintain normal operations.

Parisky KM, Agosto Rivera JL, Donelson NC, Kotecha S, Griffith LC. Reorganization of Sleep by Temperature in Drosophila Requires Light, the Homeostat, and the Circadian Clock. Curr Biol. 2016.

2016 Summer MRSEC Undergraduate Research Fellowships (SMURF)

The Division of Science wishes to announce that, in 2016, we will offer five Summer MRSEC Undergraduate Research Fellowships for Brandeis students doing undergraduate research, sponsored by the Brandeis Materials Research Science and Engineering Center.

The due date for applications is February 24, 2016, at 6:00 PM EST.

SMURF Fellowships will provide $5000 in stipend support to allow students to do summer research in MRSEC labs (housing support is not included). Students are eligible if they will be rising Brandeis sophomores, juniors, or seniors in Summer 2016 (classes of ’17, ’18, and ’19). No prior lab experience is required. A commitment from a Brandeis MRSEC member to serve as your mentor in Summer 2016 is required.

mrsec-studentThe Division of Science Summer Program will run from May 31 – August 5, 2016. Recipients are expected to be available to do full time laboratory research during that period, and must commit to presenting a poster at the final poster session (SciFest VI) on Aug 4, 2016. Five positions are available.

To apply, the application form is online: http://goo.gl/forms/ksygMGGu3p (Brandeis login required).

Questions that are not answered in the online FAQ may be addressed to Steven Karel <divsci at brandeis.edu>. Additionally, there will be a question-and-answer session about summer research funding applications on Thursday, Jan 14 at 5 pm in Gerstenzang 123.

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