Tug of war between Parkinson’s protein and growth factors

A “tug of war” situation exists between Parkinson's provocateur protein alpha-synuclein and the growth factor Read more

From stinging to soothing: fire ant venom may lead to skin treatments

Compounds derived from fire ant venom can reduce skin thickening and inflammation in a mouse model of psoriasis, Emory and Case Western scientists have Read more

Troublemaker cells predict immune rejection after kidney transplant

Evidence is accumulating that the presence of certain "troublemaker" memory T cells can predict the likelihood of belatacept-resistant immune Read more

Tug of war between Parkinson’s protein and growth factors

Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson’s disease (PD), blocks signals from an important brain growth factor, researchers have discovered.

The results were published this week in PNAS.

The finding adds to evidence that alpha-synuclein is a pivot for damage to brain cells in PD, and helps to explain why brain cells that produce the neurotransmitter dopamine are more vulnerable to degeneration.

Alpha-synuclein is a major component of Lewy bodies, the protein clumps that are a pathological sign of PD. Also, duplications of or mutations in the gene encoding alpha-synuclein drive some rare familial cases.

In the current paper, researchers led by Keqiang Ye, PhD demonstrated that alpha-synuclein binds and interferes with TrkB, the receptor for BDNF (brain derived neurotrophic factor). BDNF promotes brain cells’ survival and was known to be deficient in Parkinson’s patients. When applied to neurons, BDNF in turn sends alpha-synuclein away from TrkB.  [Ye’s team has extensively studied the pharmacology of 7,8-dihydroxyflavone, a TrkB agonist.]

A “tug of war” situation thus exists between alpha-synuclein and BDNF, struggling for dominance over TrkB. In cultured neurons and in mice, alpha-synuclein inhibits BDNF’s ability to protect brain cells from neurotoxins that mimic PD-related damage, Ye’s team found. Read more

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From stinging to soothing: fire ant venom may lead to skin treatments

Compounds derived from fire ant venom can reduce skin thickening and inflammation in a mouse model of psoriasis, Emory and Case Western scientists have shown.

The results were published on Sept. 11 in Scientific Reports.

Update: When this paper was published, Lab Land received an email providing anecdotal support for effectiveness in humans. “I have suffered with psoriasis all my life and in 2015, I went on an expedition to Central America. I got eaten alive by fire ants, as they managed to get into my socks. My psoriasis however got better for a time, and as somebody who has directly experienced fire ant venom, I strongly believe that there is a correlation between it and psoriasis.”

The findings could lead to new treatments for psoriasis, a common autoimmune skin disease. Topical steroids are now most frequently used for mild to moderate psoriasis, but they have side effects such as skin thinning and easy bruising.

Solenopsins are the main toxic components of fire ant venom. They chemically resemble ceramides, which are lipid-like molecules essential for maintaining for the barrier function of the skin. Ceramides can be found in many skin care products.

Ceramides can act as a double-edged sword, says lead author Jack Arbiser, MD, PhD, professor of dermatology at Emory University School of Medicine. Under certain conditions they can be converted by cells into S1P (sphingosine-1-phosphate), an inflammatory molecule.

Arbiser and his colleagues devised two solenopsin analogs that look like ceramides, but can’t be degraded into S1P. They then tested them in a mouse model of psoriasis, applying the compounds in a one percent skin cream for 28 days. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Troublemaker cells predict immune rejection after kidney transplant

Emory scientists have identified troublemaker cells—present in some patients before kidney transplantation—that are linked to immune rejection after transplant. Their results could guide transplant specialists in the future by helping to determine which drug regimens would be best for different groups of patients. Eventually, the findings could lead to new treatments that improve short- and long-term outcomes.

Transplant patients used to have no choice but to take non-specific drugs to prevent immune rejection of their new kidneys. While these drugs, called calcineurin inhibitors, are effective at preventing early rejection, they lack specificity for the immune system and ironically can damage the very kidneys they are intended to protect. In addition, their side effects lead to higher rates of high blood pressure, diabetes, and cardiovascular disease, ultimately shortening the life of the transplant recipient. This changed with the advent of costimulation blockers, which avoid these harmful side effects. Emory transplant surgeons Chris Larsen and Tom Pearson, together with Bristol-Myers Squibb, helped develop one of these new drugs called belatacept, which blocks signals through the costimulatory receptor CD28.

In a long-term clinical study of belatacept, kidney transplant patients tended to live longer with better transplant function when taking belatacept compared with calcineurin inhibitors. Despite these desirable outcomes, acute rejection rates were higher in patients treated with belatacept.

Andrew Adams, an Emory transplant surgeon who focuses on costimulation blockade research, notes: “While the acute rejection seen with belatacept is treatable with stronger immunosuppression, there may be long-term effects that linger and impair late outcomes.”

Most transplant centers have not yet adopted this new therapy as their standard of care because of the higher rejection rate as well as other logistical concerns, thus limiting patients’ access to potential health benefits afforded with belatacept treatment.

Adams and colleague Mandy Ford have identified certain types of memory T cells, which typically provide long-lasting immunity to infection, as potential mischief-makers in the setting of organ transplants treated with belatacept. Evidence is accumulating that the presence of certain memory T cells can predict the likelihood of “belatacept-resistant” rejection. Two recent papers in American Journal of Transplantation by Ford and Adams support this idea. Read more

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Imaging sleep drunkenness: #IHAW2017

At some point, everyone has experienced a temporary groggy feeling after waking up called sleep inertia. Scientists know a lot about sleep inertia already, including how it impairs cognitive and motor abilities, and how it varies with the time of day and type of sleep that precedes it. They even have pictures of how the brain wakes up piece by piece.

People with idiopathic hypersomnia or IH display something that seems stronger, termed “sleep drunkenness,” which can last for hours. Czech neurologist Bedrich Roth, the first to identify IH as something separate from other sleep disorders, proposed sleep drunkenness as IH’s defining characteristic.

Note: Emory readers may recall the young Atlanta lawyer treated for IH by David Rye, Kathy Parker and colleagues several years ago. Our post today is part of IH Awareness Week® 2017.

Sleep drunkenness is what makes IH distinctive in comparison to narcolepsy, especially narcolepsy with cataplexy, whose sufferers tend to fall asleep quickly. Those with full body cataplexy can collapse on the floor in response to emotions such as surprise or amusement. In contrast, people with IH tend not to doze off so suddenly, but they do identify with the statement “Waking up is the hardest thing I do all day.”

At Emory, neurologist Lynn Marie Trotti and colleagues are in the middle of a brain imaging study looking at sleep drunkenness.

“We want to find out if sleep drunkenness in IH is the same as what happens to healthy people with sleep inertia and is more pronounced, or whether it’s something different,” Trotti says. Read more

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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.

Read more

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Cancer drug discovery: targeting DNA repair

Standard anticancer treatments, such as chemotherapy, target rapidly dividing cells by damaging their DNA. A newer strategy is to undercut cancer cells’ ability to repair DNA damage.

Radiation oncologist David Yu, MD, PhD

Winship Cancer Institute investigators led by David Yu, MD, PhD have identified a distinct function in DNA double strand break repair for an enzyme called SAMHD1. Depleting or inhibiting SAMHD1 could augment anticancer treatments that induce DNA double-strand breaks, such as ionizing radiation or PARP inhibitor drugs, they suggest. Ionizing radiation is a mainstay of cancer treatment and PARP inhibitors are being developed for several cancer types.

The findings were published this week in Cell Reports (open access).

SAMHD1 was known for its ability to chop up the building blocks of DNA, and had come to the attention of virologists because it limits the ability of retroviruses such as HIV to infect some cell types. The first author of the paper, postdoc Waaqo Daddacha, PhD, previously studied SAMHD1 with virologist Baek Kim, PhD, professor of pediatrics.

Cancer researchers had already sought to harness a retroviral protein called Vpx, which viruses evolved to disable SAMHD1. Acute myeloid leukemia cells use SAMHD1 to get rid of the drug cytarabine, so Vpx can sensitize AML to that drug. The Cell Reports paper shows that virus-like particles carrying Vpx could be deployed against other types of cancer, in combination with agents that induce DNA double-strand breaks. Read more

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Update on SIV remission studies

Tab Ansari’s research at Emory/Yerkes on how an antibody treatment can push monkeys infected with SIV into remission was published in Science last year. At that time, Ansari told Lab Land about follow-up experiments to probe which immune cells are needed for this effect, which surprised many HIV/AIDS experts.

Ansari’s partner on the project, NIAID director Anthony Fauci, described the follow-up work in July at the International AIDS Society Conference in Paris. We thank Treatment Action Group’s Richard Jefferys for taking notes and posting a summary:

The approach that the researchers took was to deplete different types of immune cells in the animals controlling SIV viral load, then assess whether this led to an increase in viral replication. The experiments compared:

*Antibodies to the CD8 receptor alpha chain, which deplete CD8 T cells, natural killer T cells (NKTs) and natural killer (NK) cells

*Antibodies to the CD8 receptor beta chain, which deplete CD8 T cells

*Antibodies to CD20, which deplete B cells

According to Fauci’s slides, which are available online, there was a transient rebound in viral load with the CD8 alpha antibody and to a small degree with the CD8 beta. This suggests NKTs and NK cells are making a contribution to the observed control of SIV replication, but a role for CD8 T cells cannot be ruled out.

For comparison, a study from Guido Silvestri and colleagues at Yerkes published in 2016 found that treating SIV-infected monkeys with anti-CD8 antibodies, without stopping antiretroviral drugs, resulted in a rebound in virus levels. [They used ultrasensitive assays to detect the rebound.] However, the Yerkes team only used antibodies to the CD8 receptor alpha chain.

Read more

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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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Blood vessels and cardiac muscle cells off the shelf

Tube-forming ability of purified CD31+ endothelial cells derived from induced pluripotent stem cells after VEGF treatment.

Chunhui Xu’s lab in the Department of Pediatrics recently published a paper in Stem Cell Reports on the differentiation of endothelial cells, which line and maintain blood vessels. Her lab is part of the Emory-Children’s-Georgia Tech Pediatric Research Alliance. The first author was postdoc Rajneesh Jha.

This line of investigation could eventually lead to artificial blood vessels, grown with patients’ own cells or “off the shelf,” or biological/pharmaceutical treatments that promote the regeneration of damaged blood vessels. These treatments could be applied to peripheral artery disease and/or coronary artery disease.

Xu’s paper concerns the protein LGR5, part of the Wnt signaling pathway. The authors report that inhibiting LGR5 steers differentiating pluripotent stem cells toward endothelial cells and away from cardiac muscle cells. The source iPSCs were a widely used IMR90 line.

Young-sup Yoon’s lab at Emory has also been developing methods for the generation of endothelial cells via “direct reprogramming.”

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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