By adolescence, your brain already contains most of the neurons that you’ll have for the rest of your life. But a few regions continue to grow new nerve cells— and require the services of cellular sentinels, specialized immune cells that keep the brain safe by getting rid of dead or dysfunctional cells.
Greg Lemke’s lab described the surprising extent to which both dying and dead neurons are cleared away April 2016 in Nature.
Edward Callaway’s lab has developed a new reagent to map the brain’s complex network of connections that is 20 times more efficient than their previous version. This tool, detailed by first author Euiseok Kim in Cell Reports in April 2016, improves upon a technique called rabies virus tracing, which was originally developed by Callaway and is commonly used to map neural connections.
This dramatic improvement will help researchers illuminate aspects of brain disorders where connectivity and global processing goes awry, such as in autism, schizophrenia and some motor and neurodevelopmental diseases.
Read News ReleaseA microscope about the size of a penny is giving scientists a new window into the everyday activity of cells within the spinal cord. The new miniaturized imaging methods, described on April 28, 2016 in Nature Communications, reveal more about nervous system function and could lead to pain treatments for spinal cord injuries, chronic itch and diseases such as amyotrophic lateral sclerosis (ALS).
Salk Institute scientists showed how an FDA-approved drug boosts the health of brain cells by limiting their energy use. Like removing unnecessary lighting from a financially strapped household to save on electricity bills, the drug—called rapamycin—prolongs the survival of diseased neurons by forcing them to reduce protein production to conserve cellular energy.
Rapamycin has been shown to extend lifespan and reduce symptoms in a broad range of diseases and, at the cellular level, is known to slow down the rate at which proteins are made.
But the new Salk research, led by Salk Professor Tony Hunter and published in the journal eLife, suggests that rapamycin could also target the neural damage associated with Leigh syndrome, a rare genetic disease, and potentially other forms of neurodegeneration as well.
Previous studies on rapamycin, which blocks an energy sensor in cells, suggested that the drug prevents neurodegeneration by encouraging cells to degrade damaged components. But recent data hinted that rapamycin might also affect mitochondria, organelles that produce energy in the form of adenosine triphosphate (ATP).
Hunter, Salk Professor Rusty Gage, first author Xinde Zheng and colleagues reprogrammed skin cells from patients with Leigh syndrome into brain cells in a dish. The Leigh syndrome neurons decayed and showed clear signs of energy depletion. Meanwhile, Leigh syndrome neurons exposed to rapamycin had more ATP and showed less degeneration. By turning down the dial on protein production, the diseased neurons were able to survive longer.
The teams are continuing to investigate how rapamycin’s effect on reducing protein synthesis could be harnessed into a treatment for mitochondria-related neurodegenerative diseases.
Read News Release Read MoreWhen tweaking its architecture, the adult brain works like a sculptor— starting with more than it needs so it can carve away the excess to achieve an ideal design. That’s the conclusion of a new study that tracked developing cells in an adult mouse brain in real time.
New brain cells began with a period of overgrowth before the brain pruned back its connections. The observation, described May 2016 in Nature Neuroscience, suggests that novel cells in the adult brain have more in common with those in the embryonic brain than scientists previously thought.
While most of the brain’s billions of cells are formed before birth, Salk Professor Rusty Gage and others previously showed that in a few select areas of the mammalian brain, stem cells develop into new neurons during adulthood. In this study, his group focused on cells in the dentate gyrus, an area thought to be responsible for the formation of memories.
Gage and first author Tiago Gonçalves followed—on a daily basis—the growth of neurons over several weeks. When mice were housed in environments with lots of stimuli, the new cells grew quickly, sending out dozens of branches called dendrites which receive electrical signals from surrounding neurons. When kept in empty housing, new neurons grew slightly slower and sent out less dendrites. But, in both cases, the new dendrites began to be pruned back.
Defects in the dendrites of neurons have been linked to brain disorders like schizophrenia, Alzheimer’s, epilepsy and autism. Charting how the brain shapes these branches—both during embryonic development and in adulthood—may be the key to understanding mental health.
Read News Release Read MoreScientists at the Salk Institute and The Scripps Research Institute (TSRI) discovered two enzymes that could someday be targeted to treat type 2 diabetes and inflammatory disorders, as detailed in Nature Chemical Biology on March 28, 2016.
The discovery is unusual because the enzymes do not bear a resemblance—in their structures or amino-acid sequences—to any known class of enzymes, according to co-senior authors Alan Saghatelian, Salk professor, and Benjamin Cravatt, chair of TSRI’s Department of Chemical Physiology.
These “outlier” enzymes, called AIG1 and ADTRP, appear to break down a class of lipids Saghatelian uncovered in 2014 called fatty acid esters of hydroxy fatty acids (FAHFAs). Saghatelian had found that boosting the levels of one FAHFA lipid normalizes glucose levels in diabetic mice. In principle, inhibitors of AIG1 and ADTRP could be developed into FAHFA-boosting therapies that reduce inflammation as well as improve glucose levels and insulin sensitivity.
The labs are collaborating on further studies of the new enzymes and potential benefits of inhibiting them in mouse models of diabetes, inflammation and autoimmune disease.
Read News Release Read MoreFor more than a decade, scientists across the globe strived to replace failing pancreatic beta cells linked to immune destruction in children (type 1 diabetes) or obesity-associated diabetes in adults (type 2 diabetes). Although cells made in a dish were able to produce insulin, they were sluggish or simply unable to respond to glucose…
A molecular pathway activated in the brain during fasting halts the spread of intestinal bacteria into the bloodstream, according to work published May 2016 in the Proceedings of the National Academy of Sciences.
Salk Professor Marc Montminy, in collaboration with the labs of John Thomas and Janelle Ayres, uncovered this brain-gut signal in fruit flies, which could eventually inform the treatment of inflammatory bowel diseases in people.
To detail this pathway, first author Run Shen and colleagues studied a genetic switch in the brain called Crtc. They found that the guts of fruit flies without Crtc expressed molecules indicating that the immune system was keyed up, suggesting that without Crtc, bacteria leak from the gut into the fly’s circulation.
The normal role of Crtc is to fortify the barriers of the gut to prevent bacteria from entering the bloodstream and awakening the immune system. Without Crtc, the connections between cells that line the gut tube became disrupted, causing bacteria to leak out, activating the immune response and depleting energy reserves. The team also discovered that without the protein sNPF (found in the fly brain and with a human equivalent), the flies showed signs of gut inflammation similar to those flies missing Crtc. What’s more, the normally tight seals along the GI tract were broken down, letting bacteria out. Conversely, flies expressing more than the normal amounts of Crtc or sNPF in their neurons were able to survive longer without food and showed less disruption to the tight junctions that maintain their GI barriers. The team is conducting more experiments to understand how the neuropeptides activate the gut receptors that help protect it from bacterial invasion.
Read News Release Read MoreSalk Professor Reuben Shaw’s lab revealed how a cellular “fuel gauge” responsible for managing energy processes—a protein complex called AMPK—has an unexpected role in development. The work was published March 2016 in Genes & Development.
Shaw, first author Nathan Young and colleagues discovered that embryonic stem cells without a functioning AMPK pathway don’t execute the development process properly, creating more of one germ layer than another. This lapse turns out to be due to a loss of lysosomes, structures responsible for degrading and reusing cellular components. By turning on lysosomal genes, the team was able to restore normal development in the AMPK-deficient cells.
According to Shaw, the connection between AMPK and lysosomes reveals more about cellular growth and metabolism.
Currently, lysosome inhibitors are in dozens of clinical trials for certain cancers, even though the exact link between lysosomes and tumors is not understood. “We are decoding underlying connections that might indicate when and how cancer drugs might be useful,” says Shaw. “This work may help us make better, more specific ways of targeting lysosomes in cancer.”
Read News Release Read MoreAt noon every day, levels of genes and proteins throughout your body are drastically different than they are at midnight. Disruptions to this 24-hour cycle of physiological activity are why jet lag or a bad night’s sleep can alter your appetite and sleep patterns for days—and even contribute to conditions like heart disease and cancers.
Now, scientists led by Ronald Evans have discovered a key player—a protein called REV-ERB—that controls the strength of this circadian rhythm in mammals. The discovery, published May 2016 in Cell, is unusual in the field, as most circadian genes and proteins only shift the timing or length of the daily cycle.
The study’s first author Xuan Zhao, Evans and colleagues analyzed levels and molecular characteristics of REV-ERB in the livers of mice. After the protein’s levels peaked during the day, two other proteins, CDK1 and FBXW7, reduced REV-ERB to a low point by the middle of the night. When the team targeted these proteins to block the degradation of REV-ERB, normal daily fluctuations in gene expression were suppressed, but the timing of the cycles wasn’t affected. Altering the strength of the gene expression oscillations profoundly affected metabolism, disrupting the levels of fats and sugars in the blood. What’s more, mice that lacked REV-ERB developed fatty liver disease, stressing the importance of regulating the intensity of the cycle.
Read News Release Read More
Beyond DNA: Unlocking the Secrets of the EpigenomeA layer of regulatory information on top of DNA is proving to be as important as genes for development, health and sickness.
Tapping our Immune System’s SuperpowerWe all have a superhero—or supervillian—inside our bodies. It’s called our immune system. Every day, a healthy immune system repels a host of adversaries—bacteria, viruses, parasites—you name it!
All about town with Pablo HollsteinGrowing up in Quito, Ecuador, Pablo Hollstein was passionate—and precise —about science from an early age. 
