Fragile X: $8 million NIH grant supports next-generation neuroscience

Supported by a $8 million, five-year grant, an Emory-led team of scientists plans to investigate new therapeutic approaches to fragile X syndrome, the most common inherited intellectual disability and a major single-gene cause of autism.

Fragile X research represents a doorway to a better understanding of autism, and learning and memory. The field has made strides in recent years. Researchers have a good understanding of the functions of the FMR1 gene, which is silenced in fragile X syndrome.

Still, clinical trials based on that understanding have been unsuccessful, highlighting limitations of current mouse models. Researchers say the answer is to use “organoid” cultures that mimic the developing human brain.

The new grant continues support for the Emory Fragile X Center, first funded by the National Institutes of Health in 1997. The Center’s research program includes scientists from Emory as well as Stanford, New York University, Penn and the University of Southern California. The Emory Center will be one of three funded by the National Institutes of Health; the others are at Baylor College of Medicine and Cincinnati Children’s Hospital Medical Center.

The co-directors for the Emory Fragile X Center are Peng Jin, PhD, chair of human genetics, and Stephen Warren, PhD, William Patterson Timmie professor and chair emeritus of human genetics. In the 1980s and 1990s, Warren led an international team that discovered the FMR1 gene and the mechanism of trinucleotide repeat expansion that silences the gene. This explained fragile X syndrome’s distinctive inheritance pattern, first identified by Emory geneticist Stephanie Sherman, PhD.

“Fragile X research is a consistent strength for Emory, stretching across several departments, based on groundbreaking work from Steve and Stephanie,” Jin says. “Now we have an opportunity to apply the knowledge we and our colleagues have gained to test the next generation of treatments.”

Fragile X researchers from three Emory departments, following COVID-19 spacing guidelines in the laboratory. From left to right: Peng Jin, Gary Bassell, Zhexing Wen and Nisha Raj.

Looking ahead, a key element of the Center’s research will involve studying the human brain in “disease in a dish” models, says Gary Bassell, PhD, chair of cell biology. Nisha Raj, PhD, a postdoctoral fellow in Bassell’s lab, has been studying how FMR1 regulates localized protein synthesis at the brain’s synapses.

“What we’re learning is that there may be different RNA targets in human and mouse cells,” he says. “There’s a clear need to regroup and incorporate human cells into the research.”

Center investigator Zhexing Wen, PhD, has developed techniques for culturing brain organoids (image above), which reproduce features of human brain development in miniature. Wen, assistant professor of psychiatry and behavioral sciences, cell biology and neurology at Emory, has used organoids to model other disorders, such as schizophrenia and Alzheimer’s disease.

The organoids are formed from human brain cells, coming from induced pluripotent stem cells, which are in turn derived from patient-donated tissues. Emory’s Laboratory of Translational Cell Biology, directed by Bassell, has developed several lines of induced pluripotent stem cells from fragile X syndrome patients.

“All of the investigators are sharing these valuable resources and collaborating on multiple projects,” Bassell says.

Principal investigators in the Emory Fragile X Center are Jin, Warren, Bassell, and Wen, along with Eric Klann, PhD at New York University, Lu Chen, PhD, and 2013 Nobel Prize winner Thomas Südhof, MD. Chen and Südhof are neuroscientists at Stanford.

Co-investigators include biostatistician Hao Wu, PhD and geneticist Emily Allen, PhD at Emory, neuroscientist Guo-li Ming, MD, PhD, at University of Pennsylvania, and biomedical engineer Dong Song, PhD, at University of Southern California.

Allen, Warren and Jin are part of an additional grant to Baylor, Emory and University of Michigan investigators, who are focusing on FXTAS (fragile X-associated tremor-ataxia syndrome) and FXPOI (fragile X-associated primary ovarian insufficiency). These are conditions that affect people with fragile X premutations.

Fragile X syndrome is caused by a genetic duplication on the X chromosome, a “triplet repeat” in which a portion of the gene (CGG) gets repeated again and again. Fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges. About a third of children affected have characteristics of autism, such as problems with eye contact, social anxiety, and delayed speech.

The award for the Emory Fragile X Center is administered by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with funding from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

Posted on October 2, 2020 by Quinn Eastman in Neuro Leave a comment

‘Genetic doppelgangers:’ Emory research provides insight into two neurological puzzles

An international team led by Emory scientists has gained insight into the pathological mechanisms behind two devastating neurodegenerative diseases. The scientists compared the most common inherited form of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) with a rarer disease called spinocerebellar ataxia type 36 (SCA 36).

Both of the diseases are caused by abnormally expanded and strikingly similar DNA repeats. However, ALS progresses quickly, typically killing patients within a year or two, while the disease progression of SCA36 proceeds more slowly over the course of decades. In ALS/FTD it appears that protein products can poison cells in the nervous system. Whether similar protein products exist in SCA36 is not known.

What Zachary McEachin, PhD, and Gary Bassell, PhD, from Emory’s Department of Cell Biology, along with a team of collaborators at Emory, the Mayo Clinic in Jacksonville, Florida, and internationally from Spain and Japan, discovered have provided a new paradigm for thinking about how aberrant protein species are formed. Regardless of the disparate clinical outcomes between these diseases, this research could broaden the avenue of research toward genetically targeted treatments for such related neurodegenerative diseases.

Their study, published Tuesday in Neuron, provides a guide to types of protein that build up in brain cells in both disorders, and which should be reduced if the new mode of treatment is working in clinical trials.

“We are thinking of these diseases as genetic doppelgängers,” says McEachin, a postdoctoral fellow in Bassell’s lab. “By that, I mean they are genetically similar, but the neurodegeneration progresses differently for each disease. We can use this research to understand each of the respective disorders much better — and hopefully help patients improve their quality of life down the road with better treatments.”

An estimated 16,000 people in the United States have ALS, a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. The most common inherited form of ALS/FTD occurs because there is an abnormally expanded repeat of six DNA “letters” stuck into a gene called c9orf72.

Posted on May 5, 2020 by Wayne Drash in Neuro, Uncategorized Leave a comment

NINDS supporting Emory/UF work on myotonic dystrophy

A collaboration we wrote about back in 2017, between Emory cell biology chair Gary Bassell and University of Florida neurogeneticist Eric Wang, is taking off.

The National Institute of Neurological Disorders and Stroke has awarded Bassell’s and Wang’s laboratories $2.2 million over five years to examine the neuronal function of Muscleblind-like proteins, which play key roles in myotonic dystrophy.

Gary Bassell and Eric Wang have been collaborating on myotonic dystrophy research

The classic symptom for myotonic dystrophy is having trouble releasing one’s grip on a doorknob, but it is a multi-system disorder, caused by expanded DNA triplet or quadruplet repeats. RNA from the expanded repeats is thought to bind and sequester Muscleblind-like proteins, leading to an impaired process of RNA splicing.

Bassell says the project is expected to clarify how Muscleblind-like proteins regulate RNA localization in neurons and also identify therapeutic targets. In recent years, the DM research community has been paying increasing attention to neurologic symptoms.

Posted on February 24, 2020 by Quinn Eastman in Neuro Leave a comment

Stage fright: don’t get over it, get used to it

Stage fright: don’t get over it, get used to it, advises Emory neuroscientist Anwesha Banerjee in her recent talk at TEDx Decatur. Many can feel empathy with the situation Banerjee describes. It was her first public presentation eight years ago, facing “a room full of scientists, who for whatever reason, did not look very happy that day.”

“What if I fail in front of the crowd? What if everybody thinks I’m an idiot?”

That feeling of scrutiny might have an evolutionary relationship to the fear of being eaten by a predator, she speculates.

Through participating in Toastmasters International, she has made public speaking more of a habit. She contrasts the two parts of the brain: the amygdala, tuner of emotional responses, with the basal ganglia, director of habits.

“I still get stage fright,” she says. “In fact, I have it right now, thinking how all you predators might try to eat me up! But my brain pays less attention to it.”

Banerjee is a postdoctoral scientist in cell biologist Gary Bassell’s lab, studying myotonic dystrophy. In 2017, she was funded by the Myotonic Dystrophy Foundation to create a mouse model of the neurological/sleep symptoms of myotonic dystrophy.

Posted on November 13, 2019 by Quinn Eastman in Neuro Leave a comment

Probing hyperexcitability in fragile X syndrome

Researchers at Emory University School of Medicine have gained insight into a feature of fragile X syndrome, which is also seen in other neurological and neurodevelopmental disorders.

In a mouse model of fragile X syndrome, homeostatic mechanisms that would normally help brain cells adjust to developmental changes don’t work properly. This helps explain why cortical hyperexcitability, which is linked to sensory sensitivity and seizure susceptibility, gradually appears during brain development.

Studying a model of fragile X syndrome, Emory researchers were looking at neurons displaying single spiking and multi-spiking behavior.

These physiological insights could help guide clinical research and efforts at early intervention, the scientists say. The results were published Feb. 5 by Cell Reports (open access).

Fragile X syndrome is the most common inherited form of intellectual disability and a leading single-gene cause of autism. Individuals with fragile X syndrome often display sensory sensitivity and some — about 15 percent— have seizures.

Scientists’ explanation for these phenomena is cortical hyperexcitability, meaning that the response of the cortex (the outer part of the brain) to sensory input is more than typical. Cortical hyperexcitability has also been observed in the broader category of autism spectrum disorder, as well as migraine or after a stroke.

At Emory, graduate student Pernille Bülow forged a collaboration between Peter Wenner, PhD and Gary Bassell, PhD. Wenner, interested in homeostatic plasticity, and Bassell, an expert in fragile X neurobiology, wanted to investigate why a mechanism called homeostatic intrinsic plasticity does not compensate for the changes in the brain brought about in fragile X syndrome. More here.

Posted on February 8, 2019 by Quinn Eastman in Neuro Leave a comment

Fragile X files — expanded

A genetic disorder caused by silencing of a gene on the X chromosome, fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges.

Amy Talboy, MD

The gene responsible for fragile X syndrome, the most common inherited form of intellectual disability, was identified more than 25 years ago. Emory genetics chair Stephen Warren played a major role in achieving that milestone. His work led to insights into the molecular details of learning and memory, and nationwide clinical trials — which have a more complicated story.

Treating the molecular basis of a neurodevelopmental disorder, instead of simply addressing symptoms, is a lofty goal – one that remains unfulfilled. Now a new study, supported by the National Institute of Neurological Disorders and Stroke, is reviving a pharmacological strategy that Warren had a hand in developing.

“This is a very well thought out approach to studying changes in language and learning in children who are difficult to test,” says Amy Talboy, medical director of Emory’s Down Syndrome and Fragile X clinics, who is an investigator in the NINDS study. “It could change how we conduct these types of studies in the future.” Read more

Posted on October 23, 2018 by Quinn Eastman in Neuro Leave a comment

Fragile X: preclinical portfolio for PI3k drug strategy

Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.

The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.

When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.

The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.

Video from the iBook “Basic Science Breakthroughs: Fragile X Syndrome”. Narration by Emory genetics chair Stephen Warren, whose team identified the gene responsible for fragile X.

“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.

“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”

The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.

While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.

With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.

Warren played a major role in developing the mGluR5 approach and Emory investigators were part of those studies. More recently, clinical trials for one of the mGluR5 medications were revived in younger children and Emory is a participating site. Also, see this 2016 discussion in Spectrum with Elizabeth Berry-Kravis on the fragile X mouse model; Bassell, Gross and Gourley have made some inroads on the limitations Berry-Kravis describes.

Posted on July 19, 2018 by Quinn Eastman in Neuro Leave a comment

The journey of a marathon sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to follow. What they found could provide benefits for patients with the genetic disease myotonic dystrophy (DM) and possibly the sleep disorder idiopathic hypersomnia (IH).

The classic symptom for DM is: someone has trouble releasing their grip on a doorknob. However, the disease does not only affect the muscles. Clinicians have recognized for years that DM can result in disabling daytime sleepiness and sometimes cognitive impairments. At the Myotonic Dystrophy Foundation meeting in September, a session was held gathering patient input on central nervous system (CNS) symptoms, so that future clinical trials could track those symptoms more rigorously.

Emory scientists are investigating this aspect of DM. Cell biology chair Gary Bassell was interested in the disease, because it’s a triplet repeat disorder, similar to fragile X syndrome, yet the CNS mechanisms and symptoms are very different. In DM, an expanded triplet or quadruplet repeat produces toxic RNA, which disrupts the process of RNA splicing, affecting multiple cell types and tissues.

Rye at San Francisco myotonic dystrophy meeting. Photo courtesy of Hypersomnia Foundation.

Neurologist and sleep specialist David Rye also has become involved. Recall Rye’s 2012 paper in Science Translational Medicine, which described a still-mysterious GABA-enhancing substance present in the spinal fluid of some super-sleepy patients. (GABA is a neurotransmitter important for regulating sleep.)

In seven of those patients, his team tested the “wake up” effects of flumazenil, conventionally used as an antidote to benzodiazepines. One of those patients was an Atlanta lawyer, whose recovery was later featured in the Wall Street Journal and on the Today Show. It turns out that another one of the seven, whose alertness increased in response to flumazenil, has DM.

In an overnight sleep exam, this man slept for 12 hours straight – the longest of the seven. But an IH diagnosis didn’t fit, because in the standard “take a nap five times” test, he didn’t doze off very quickly. He became frustrated with the stimulants he was given and sought treatment elsewhere, Rye says. Lab Land doesn’t have all the details of this patient’s history, but eventually he was diagnosed with DM, which clarified his situation. Read more

Posted on December 1, 2017 by Quinn Eastman in Neuro Leave a comment

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

Posted on July 13, 2017 by Quinn Eastman in Neuro Leave a comment

‘Matchmaker’ role for protein behind SMA

Motor neurons connect the spinal cord to the muscles. They can be a meter long in adult humans. SMA (spinal muscular atrophy) affects approximately 1 in 10,000 babies. It impairs the ability to move and breathe, and in its most severe form, kills before the age of two.

A puzzling question has lurked behind SMA (spinal muscular atrophy), the leading genetic cause of death in infants.

The disorder leads to reduced levels of the SMN (survival of motor neurons) protein, which is thought to be involved in processing RNA, something that occurs in every cell in the body. So why does interfering with a process that happens everywhere affect motor neurons first?

Scientists at Emory University School of Medicine have been building a case for an answer. It’s because motor neurons have long axons. And RNA must be transported to the end of the axons for motor neurons to survive and keep us moving, eating and breathing.

Now the Emory researchers have a detailed picture for what they think the SMN protein is doing, and how its deficiency causes problems in SMA patients’ cells. The findings are published in Cell Reports.

Wilfried Rossoll, PhD in the lab.

“Our model explains the specificity — why motor neurons are so vulnerable to reductions in SMN,” says Wilfried Rossoll, PhD, assistant professor of cell biology at Emory University School of Medicine [and soon moving to the Mayo Clinic in Jacksonville]. “What’s new is that we have a mechanism.”

Rossoll and his colleagues showed that the SMN protein is acting like a “matchmaker” for messenger RNA that needs partners to transport it into the cell axon.

RNA carries messages from DNA, huddled in the nucleus, to the rest of the cell so that proteins can be produced locally. But RNA can’t do that on its own, Rossoll says. In the paper, the scientists call SMN a “molecular chaperone.” That means SMN helps RNA hook up with processing and transport proteins, but doesn’t stay attached once the connections are made.

“It loads the truck, but it’s not on the truck,” Rossoll says. [Read the rest of Emory’s press release here.]

He also tells me that even though the two diseases affect very different age groups, SMA and ALS (amyotrophic lateral sclerosis) have two things in common: they both affect motor neurons and they both involve proteins that transport RNA. He says an emerging idea in the field is that SMA represents a problem of “hypo-assembly” while ALS is a problem of “hyper-assembly.”

Posted on February 15, 2017 by Quinn Eastman in Neuro Leave a comment

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