Repurposing a transplant drug for bone growth

The transplant immunosuppressant drug FK506, also known as tacrolimus or Prograf, can stimulate bone formation in both cell culture and animal Read more

Beyond the amyloid hypothesis: proteins that indicate cognitive stability

If you’re wondering where Alzheimer’s research might be headed after the latest large-scale failure of a clinical trial based on the “amyloid hypothesis,” check this Read more

Mother's milk is OK, even for the in-between babies

“Stop feeding him milk right away – just to be safe” was not what a new mother wanted to hear. The call came several days after Tamara Caspary gave birth to fraternal twins, a boy and a girl. She and husband David Katz were in the period of wonder and panic, both recovering and figuring out how to care for them. “A nurse called to ask how my son was doing,” says Caspary, a developmental Read more

Neuro

Enhancing the brain’s clean up crews

Enhancing the brain’s own clean-up crews could be a strategy for handling the toxic proteins driving several neurodegenerative diseases, new research suggests.

Astrocytes, an abundant supportive cell type in the brain, are better than neurons at disposing of mutant huntingtin, the toxic protein that drives Huntington’s disease pathology, Xiao-Jiang Li and colleagues report in this week’s PNAS.

One reason why astrocytes are better at toxic protein defense than neurons is: they have less of an inhibitory protein called HspBP1. The scientists show that using CRISPR/Cas9 to “knock down” HspBP1 can help neurons get rid of mutant huntingtin and reduce early pathological signs.

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Granulins treasure not trash – potential FTD treatment strategy

Emory University School of Medicine researchers have developed tools that enable them to detect small proteins called granulins for the first time inside cells. Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously unclear.

FTD is an incurable neurodegenerative disease and the most common type of dementia in people younger than 60. Genetic variants in the granulin gene are also a risk factor for Alzheimer’s disease and Parkinson’s disease, suggesting this discovery may have therapeutic potential for a broad spectrum of age-related neurodegenerative diseases.

The results were published August 9 by the journal eNeuro (open access).

Thomas Kukar, PhD

Some neuroscientists believed that granulins were made outside cells, and even could be toxic under certain conditions. But with the newly identified tools, the Emory researchers can now see granulins inside cells within lysosomes, which are critical garbage disposal and recycling centers. The researchers now propose that granulins have important jobs in the lysosome that are necessary to maintain brain health, suppress neuroinflammation, and prevent neurodegeneration.

Problems with lysosomes appear in several neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

“A lysosomal function for granulins is exciting and novel.  We believe it may provide an explanation why decreased levels of granulins are linked to multiple neurodegenerative diseases, ranging from frontotemporal dementia to Alzheimer’s,” says senior author Thomas Kukar, PhD, assistant professor of pharmacology and neurology and the Emory University Center for Neurodegenerative Disease. Read more

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Insight into brain + learning via ‘friend of fragile X’ gene

We can learn a lot about somebody from the friends they hang out with. This applies to people and also to genes and proteins. Emory scientists have been investigating a gene that we will call — spoiler alert — “Friend of fragile X.”

Fragile X syndrome is the most common inherited form of intellectual disability, studied by research teams around the world with drug discovery and clinical trials in mind. It is caused by a disruption of the gene FMR1.

In an independent form of inherited intellectual disability found in a small number of Iranian families, a gene called ZC3H14 is mutated. Two papers from Ken Moberg, PhD, associate professor of cell biology, Anita Corbett, PhD, professor of biology and colleagues show that FMR1 and ZC3H14 are, in effect, friends.

The findings provide new insight into the function of FMR1 as well as ZC3H14; the evidence comes from experiments performed in fruit flies and mice. The most recent paper is in the journal Cell Reports (open access), published this week.

The scientists found that the proteins encoded by FMR1 and ZC3H14 stick together in cells and they hang out in the same places. The two proteins have related functions: they both regulate messenger RNA in neurons, which explains their importance for learning and memory.

The fragile X protein (FMRP) was known to control protein production in response to signals arriving in neurons, but the Cell Reports paper shows that FMRP is also regulating the length of  “tails” attached to messenger RNAs – something scientists did not realize, even after years of studying FMRP and fragile X, Moberg says.

To be sure, FMRP interacts with many proteins and appears to be a critical gatekeeper. Emory geneticist Peng Jin, who has conducted his share of research on this topic, says that “FMRP must be very social and has a lot of friends.” More here.

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Drug discovery: selective anti-inflammatory approach to AD

Anyone familiar with Alzheimer’s disease research can say what a challenge drug development has been. In Emory’s Department of Pharmacology, Thota Ganesh is focusing on an anti-inflammatory approach. Ganesh’s work has been supported by the Alzheimer’s Drug Discovery Foundation and more recently by a five-year, $3.6 million grant from the National Institute on Aging.

Medicinal chemist Thota Ganesh, PhD, is focusing on an anti-inflammatory approach to Alzheimer’s disease, targeting the prostaglandin receptor EP2.

An assistant professor at Emory since 2011, he is continuing research he undertook with Ray Dingledine on EP2 antagonists. In animals, they showed that this class of compounds could reduce injury to the brain after a prolonged seizure. Since then, they have shown that EP2 antagonists have similar effects in protecting against organophosphate pesticides/nerve agents.

EP2 is one of the four receptors for prostaglandin E2, a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Before Ganesh and colleagues from the Emory Chemical Biology Discovery Center started looking for them, chemicals that could block EP2 selectively were not available.

Their idea is: blocking EP2 is a better strategy than the more general approach of going after prostaglandins, the targets for non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and celecoxib (Celebrex). Read more

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Emory neuro-researchers in Alzforum

Just a shoutout regarding Emory folks in Alzforum, the research news site focusing on Alzheimer’s and other neurodegenerative disorders.

Alzforum recently highlighted proteomics wizard Nick Seyfried’s presentation at a June meeting in Germany (Alzheimer’s Proteomics Treasure Trove). This includes work from the Emory ADRC and Baltimore Longitudinal Study of Aging that was published in Cell Systems in December: the first large-scale systems biology analysis of post-mortem brain proteins in Alzheimer’s. The idea is to have a fresh “unbiased” look at proteins involved in Alzheimer’s.

Also, neuroscientists Malu Tansey and Tom Kukar have been teaming up to provide detailed comments on papers being reported in Alzforum. Here’s one on inflammation related to gene alterations in frontotemporal dementia, and another on auto-immune responses in Parkinson’s.

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Big data with heart, for psychiatric disorders

Imagine someone undergoing treatment by a psychiatrist. How do we know the treatment is really working or should be modified?

To assess whether the patient’s condition is objectively improving, the doctor could ask him or her to take home a heart rate monitor and wear it continuously for 24 hours. An app connected to the monitor could then track how much the patient’s heart rate varies over time and how much the patient moves.

Heart rate variability can be used to monitor psychiatric disorders

MD/PhD student Erik Reinertsen is the first author on two papers in Physiological Measurement advancing this approach, working under the supervision of Gari Clifford, interim chair of Emory’s Department of Biomedical Informatics.

Clifford’s team has been evaluating heart rate variability and activity as a tool for monitoring both PTSD (post-traumatic stress disorder) and schizophrenia. Clifford says his team’s research is expanding to look at treatment-resistant depression and other mental health issues.

For clinical applications, Clifford emphasizes that his plans focus on tracking disease severity for patients who are already diagnosed, rather than screening for new diagnoses. His team is involved in much larger studies in which heart rate data is being combined with physical activity data from smart watches, body patches, and clinical questionnaires, as well as other behavioral and exposure data collected through smartphone usage patterns.

Intuitively, heart rate variability makes sense for monitoring PTSD, because one of the core symptoms is hyperarousal, along with flashbacks and avoidance or numbness. However, it turns out that the time that provides the most information is when heart rate is lowest and study participants are most likely asleep, or at their lowest ebb during the night.

Home sleep tests generate a ton of information, which can be mined. This approach also fits into a trend for wearable medical technology, recently highlighted in STAT by Max Blau (subscription needed).

The research on PTSD monitoring grows out of work by cardiologists Amit Shah and Viola Vaccarino on heart rate variability in PTSD-discordant twin veterans (2013 Biological Psychiatry paper). Shah and Vaccarino had found that low frequency heart rate variability is much less (49 percent less) in the twin with PTSD. Genetics influences heart rate variability quite a bit, so studying twins allows those factors to be accounted for. Read more

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Unlocking schizophrenia biology via genetics

Kristen Thomas, PhD, now a postdoctoral fellow at St Jude Children’s Research Hospital

Schizophrenia genetics and its complexities are beginning to yield to large genome-wide studies. One of the recently identified top risk loci, miR 137, can be seen as a master key that unlocks other doors. The Mir 137 locus encodes a micro RNA that regulated hundreds of other genes, and several of those are also linked to schizophrenia.

Earlier this month, Emory’s chair of cell biology Gary Bassell and former graduate student Kristen Thomas published a paper in Cell Reports analyzing how perturbing Mir 137 affects signaling in neurons. Inhibiting Mir 137 blocked neurons’ responses to neuregulin and BDNF, well-known growth factors.

“We think a particularly interesting aspect of our paper is that it links miR137, neuregulin and ErbB4 receptor: three molecules with known genetic risk for schizophrenia,” Bassell writes. Read more

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Brain circuitry linked to social connection and desire to cuddle

Guest post from Neuroscience graduate student Amielle Moreno.

Why do scientists know more about the brain during fear than love? Behaviors such as startling and freezing in response to a fearful stimulus are rapid, vary little between subjects, and are easy to interpret. Things get messy when individuals show variability. Social behavior, like intimate partner selection and mating, has a lot of variability. To researchers willing to explore the neuroscience of love and mating, the stage is set for major discoveries.

A recent research study published in Nature from the Liu and Young laboratories at Emory and Yerkes uncovered a dynamic conversation between two brain regions during intimate behavior. The new findings in prairie voles explore the brain connections behind social connections. Read more

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Drug discovery: Alzheimer’s and Parkinson’s spurred by same enzyme

Alzheimer’s disease and Parkinson’s disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That’s how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson’s.

Keqiang Ye, PhD

In both Alzheimer’s (AD) and Parkinson’s (PD), a sticky and sometimes toxic protein forms clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies. Here is a thorough review of alpha-synuclein’s role in Parkinson’s disease.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it both more sticky and more toxic. In addition, they have found that AEP similarly processes beta-amyloid, another bad actor in Alzheimer’s, and drugs that inhibit AEP have beneficial effects in Alzheimer’s animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein as it does toward tau.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Ye says. “We reasoned that if AEP cuts Tau, it’s very likely that it will cut alpha-synuclein too.”

A particular chunk of alpha-synuclein produced by AEP’s scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye’s team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can’t cut it is less toxic. Read more

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Seeing the nuts and bolts of neurons

Cool photo alert! James Zheng’s lab at Emory is uncommonly good at making photos and movies showing how neurons remodel themselves. They recently published a paper in Journal of Cell Biology showing how dendritic spines, which are small protrusions on neurons, contain concentrated pools of G-actin.

Actin, the main component of cells’ internal skeletons, is a small sturdy protein that can form long strings or filaments. It comes in two forms: F-actin (filamentous) or G-actin (globular). It is not an exaggeration to call F- and G-actin neurons’ “nuts and bolts.”

Think of actin monomers like Lego bricks. They can lock together in regular structures, or they can slosh around in a jumble. If the cell wants to build something, it needs to grab some of that slosh (G-actin) and turn them into filaments. Remodeling involves breaking down the filaments.

At Lab Land’s request, postdoc and lead author Wenliang Lei picked out his favorite photos of neurons, which show F-actin in red and G-actin in green. Zheng’s lab has developed probes that specifically label the F- and G- forms. Where both forms are present, such as in the dendritic spines, an orange or yellow color appears.

Why care about actin and dendritic spines?

*The Journal of Cell Biology paper identified the protein profilin as stabilizing neurons’ pool of G-actin. Profilin is mutated in some cases of ALS (amyotrophic lateral sclerosis), although exactly how the mutations affect actin dynamics is now under investigation.

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