Neuro-ophthalmologist Nancy Newman’s 2017 Dean’s Distinguished Faculty Lecture and Award were unexpectedly timely. Her talk on Tuesday was a tour of her career and mitochondrial disorders affecting vision, culminating in a description of gene therapy clinical trials for the treatment of Leber’s hereditary optic neuropathy.
The sponsor of those studies, Gensight Biologics, recently presented preliminary data on a previous study of their gene therapy at the American Academy of Neurology meeting in April. Two larger trials Read more
Our recent news item on Emory pathologist Keqiang Ye’s obesity-related researchÂ (Molecule from trees helps female mice only resist weight gain) understatesÂ how many disease models the proto-drugÂ he and his colleagues have discovered, 7,8-dihydroxyflavone, can be beneficial in.Â We doÂ mentionÂ that Ye’s partners in Australia and Shanghai are applying to begin phase IÂ clinical trials with a close relative of 7,8-dihydroxyflavone in neurodegenerative diseases.
Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.
Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.
Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.
The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didnâ€™t develop tumors any faster than normal, and they didnâ€™t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1â€™s role in regulating blood vessel growth. What they did have was problems with spatial memory.
In the 1990s, neuroscientists identified a class of drugs that showed promise in the area of stroke. NMDA receptor antagonists could limit damage to the brain in animal models of stroke. But one problem complicated testing the drugs in a clinical setting: the side effects included disorientation and hallucinations.
Now researchers have found a potential path around this obstacle. The results were published in Neuron.
â€œWe have found neuroprotective compounds that can limit damage to the brain during ischemia associated with stroke and other brain injuries, but have minimal side effects,â€ says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine.
â€œThese compounds are most active when the pH is lowered by biochemical processes associated with injury of the surrounding tissue. This is a proof of concept study that shows this mechanism of action could potentially be exploited clinically in several conditions, such as stroke, traumatic brain injury and subarachnoid hemorrhage.â€ Read more
A new paper in PNAS from geneticist Steve Warren and colleagues illustratesÂ the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]
Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.
However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warrenâ€™s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X proteinâ€™s multifaceted functions. Read more
The researchers examined neurons in the orbitofrontal cortex, a region of the brain thought to be important for â€œlinking reward to hedonic experience.â€ It was known that stimulants such as cocaine can cause the loss of dendritic spines: small protrusions that are critical for communication and interaction between neurons.
â€œTo make an analogy, itâ€™s like a tree losing some of its leaves,â€ Gourley writes. â€œLaurenâ€™s work shows for the first time that if cocaine is given in adolescence, it can cause the loss of dendrite arbors â€“ as if entire branches are being cut from the tree.â€
The mice are exposed to cocaine over the course of five days in early adolescence, and then their behavior is studied in adulthood. This level of cocaine exposure leads to impairments in instrumental task reversal, a test where mice need to change their habits (which chamber they poke their noses into) to continue receiving food pellets.
Just before Thanksgiving, Slate writer Katy Waldman hadÂ a piece summarizing theÂ growing body of evidenceÂ thatÂ linguistic metaphors reflect how we actually use our brains.
Emory neuroscientist Krish Sathian and his colleagues have been major contributors to thisÂ field (“conceptual metaphor theory”). In 2012, he and Simon LaceyÂ published their brain imaging study, which found thatÂ when peopleÂ listened to sentences involving touch metaphors (“havingÂ a rough day”), the parts of the brain involved in the sense of touch were activated. NPR’s Jon Hamilton talked about these findings with him in 2013.
At the recent Society for Neuroscience meeting, Sathian discussed his team’s ongoing work on how the brain processes metaphors that make references to body parts (head, face, arm, hand, leg, foot), as part of a nano symposium on language.
Chorioamnionitis is a complication of pregnancy: inflammation of the membranes surrounding the fetus, caused by a bacterial infection. It has the potential to inflict damage to the brain of the fetus, especially when combined with fetal hypoxia, and is a known risk factor for developing cerebral palsy.
Chia-Yi (Alex) Kuan and his team, who study fetal brain injury in the Department of Pediatrics, have a new paper in Journal of Neuroscience on a strategy for inhibiting fetal brain inflammation. Postdoctoral fellows Dianer Yang, Yu-Yo Sun and Siddhartha Kumar Bhaumik are co-first authors.
The researchers show that a typeÂ of immune cells called Th17 cells seems to be driving inflammation because the rest of the fetal immune system is still immature. A marker of Th17 cells is elevated in blood samples from human infants with chorioamnionitis, the researchers found. Th17 cells are thought to be important for both autoimmunity and anti-microbial responses.
A drug called fingolimod, which stops immune cells from circulating out of the lymph nodes, was effective in reducing inflammation-induced fetal brain injury in animal models. Fingolimod has been approved by the FDA for use with multiple sclerosis and has been studied in clinical trials of kidney transplantation. The authors write that it may be a potential add-on to hypothermia as a treatment for infants in danger of hypoxia + infection-induced brain damage.
Pathologist Keqiang Ye and his colleagues have been studying the functions of an enzyme called AEP, or asparagine endopeptidase, in the brain. AEP is activated by acidic conditions, such as those induced by stroke or seizure.
AEP is a protease. That means it acts as a pair of scissors, snipping pieces off other proteins. In 2008, his laboratory published a paper in Molecular Cell describing how AEPâ€™s acid-activated snipping can unleash other enzymes that break down brain cellsâ€™ DNA.
Following a hunch that AEP might be involved in neurodegenerative diseases, Yeâ€™s team has discovered that AEP also acts on tau, which forms neurofibrillary tangles in Alzheimerâ€™s disease.
â€œWe were looking for additional substrates for AEP,â€ Ye says. â€œWe knew it was activated by acidosis. And we had readÂ in the literature that the aging brain tends to be more acidic, especially in Alzheimerâ€™s.â€
The findings, published in Nature Medicine in October, point to AEP as a potential target for drugs that could slow the advance of Alzheimerâ€™s, and may also lead to improved diagnostic tools. Read more