Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth. The results were published in the journal Cell Reports. “The beauty of using organoids is that they allow us to Read more

The earliest spot for Alzheimer's blues

How the most common genetic risk factor in AD interacts with the earliest site of neurodegeneration Read more

Make ‘em fight: redirecting neutrophils in CF

Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus. Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more

Department of Human Genetics

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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NGLY1 update

Emory Medicine readers may remember the Stinchcombs, a Georgia family caring for two daughters with a genetic neurological/developmental disorder called NGLY1 deficiency. We found their efforts to care for their daughters inspiring.

The rapid discovery of several children with NGLY1 deficiency, facilitated by social media, has led to a wave of research. Two recent papers represent advances toward finding treatments.

In PLOS Genetics, Japanese scientists showed that deleting the ENGase gene can partially rescue problems created by NGLY1 deficiency in a mouse model (RIKEN press release). That implies drugs that inhibit the ENGase enzyme might have similar positive effects.

Scientists knew that the NGLY1 enzyme removes chains of sugars from misfolded proteins that are stalled in cells’ production pipeline. ENGase is another enzyme that acts on those sugar chains, and its absence compensates for the lack of NGLY1. Read more

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Nerve gas, angel dust and genetic epilepsy

Last week, Lab Land noticed similarities between two independent lines of research from the Escayg and Traynelis/Yuan labs at Emory. Both were published recently and deal with rare forms of genetic epilepsy, in which molecular understanding of the cause leads to individualized treatment, albeit with limited benefit.

Both conditions are linked to an excess of neuronal excitation, and both can be addressed using medications that have also been tested for Alzheimer’s. A critical difference is that memantine is FDA-approved for Alzheimer’s, but huperzine A is not.

What condition? Dravet syndrome/GEFS+ Epilepsy-aphasia syndrome
What gene is mutated? SCN1A – sodium ion channel GRIN2A – NMDA receptor subunit
What is the beneficial drug? Huperzine A Memantine
How does the drug work? Acetylcholinesterase inhibitor NMDA receptor antagonist
Other drugs that use the same mechanism Alzheimer’s medications such as donepezil

Irreversible + stronger: insecticides, nerve gas

Ketamine, phencyclidine (aka PCP)
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Strain differences in Zika infection genes

Scientists have revealed molecular differences between how the African and Asian strains of Zika virus infect neural progenitor cells. The results could provide insights into the Zika virus’ recent emergence as a global health emergency, and also point to inhibitors of the p53 pathway as potential leads for drugs that could protect brain cells from cell death.

The findings, from the Emory/Johns Hopkins/Florida State team that showed this spring that neural progenitor cells are particularly vulnerable to Zika infection (related paper), were published this week in Nucleic Acid Research. The manuscript was also posted on BioRxiv before publication.

Zika infection genes

Overlap in gene expression changes when neural progenitor cells are infected by African or Asian strains of Zika virus. Diagram from Nucleic Acids Research via Creative Commons.

Zika virus was first discovered in Uganda in the 1940s, and two distinct lineages of Zika diverged sometime in the second half of the 20th century: African and Asian. The strains currently circulating in the Western Hemisphere, which have been linked to microcephaly in infants and Guillain-Barre syndrome in adults, are more closely related to the Asian lineage.

The research team catalogued and compared genes turned on and off by Asian and African strains of Zika virus, as well as dengue virus, in human neural progenitor cells. The authors describe dengue as inducing more robust changes in gene expression than either strain of Zika. Although they show that dengue can infect neural progenitor cells like Zika can, dengue infection does not stunt the cells’ growth or lead to cell death.

“This shows that the differences between Zika and dengue are not at the level of being able to infect neural progenitors, but more about the harm Zika causes when it does infect those cells,” says senior author Peng Jin, PhD, professor of human genetics at Emory University School of Medicine. Read more

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HD monkeys display full spectrum of symptoms seen in humans

Transgenic Huntington’s disease monkeys display a full spectrum of symptoms resembling the human disease, ranging from motor problems and neurodegeneration to emotional dysregulation and immune system changes, scientists at Yerkes National Primate Research Center, Emory University report.

The results, published online in the journal Brain, Behavior and Immunity, strengthen the case that transgenic Huntington’s disease monkeys could be used to evaluate emerging treatments (such as this) before launching human clinical trials.

“Identifying emotional and immune symptoms in the HD monkeys, along with previous studies demonstrating their cognitive deficits and fine motor problems, suggest the HD monkey model embodies the full array of symptoms similar to human patients with the disease,” says Yerkes research associate Jessica Raper, PhD, lead author of the paper. Read more

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Four take-home thoughts on NGLY1

Please check out our feature in Emory Medicine magazine about two sisters with NGLY1 deficiency. This rare genetic disorder was identified only a few years ago, and now a surge of research is directed toward uncovering its mysteries.

  1. The Stinchcombs are amazing. Seth Mnookin’s July 2014 piece in the New Yorker, and especially, his comments at the end of an interview with The Open Notebook drove me to contact them. “The father cares for the two girls with this disease full time. The mother is working insane hours. And while all this is going on, they’re the most good-natured … I don’t know, they just seem like they’re happy.”
  1. Several research teams around the world are investigating NGLY1 deficiency and potential remedies. For the magazine article, I talked with Emory geneticist Michael Gambello, Hudson Freeze at Sanford Burnham and Lynne Wolfe at the NIH Undiagnosed Diseases Program. Even more: the Grace Science Foundation, established by the Wilsey family, is supporting research at Retrophin/Notre Dame and Gladstone/UCSF. The independent Perlstein lab is investigating NGLY1 deficiency in fruit flies (reminiscent of Emory research from a decade ago on Fragile X syndrome).
  1. There’s a long road ahead for rare genetic disorders such as NGLY1 deficiency. That’s why the title that EM editor Mary Loftus came up with, “In time to help Jessie,” is so poignant. When I read Abby Goodnough’s New York Times piece on RCDP, which is a rare inherited bone disease that also involves seizures, I thought: “That could be NGLY1 in ten years.” Still, progress is possible, as demonstrated by this recent NEJM report on exome sequencing and neurometabolic disorders from British Columbia.

Read more

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Rare inherited musculoskeletal disorder illustrates broader themes

More than fifteen years ago, Emory geneticist William Wilcox was a visiting professor in Montevideo, Uruguay. There he worked with local doctors, led by Roberto Quadrelli, to study a family whose male members appeared to have an X-linked inherited disorder involving heart disease and musculoskeletal deformities.

In March 2016, Wilcox and his colleagues reported in Circulation: Cardiovascular Genetics that they had identified the genetic mutation responsible for the disorder, called “Uruguay syndrome.” His former postdoc Yuan Xue, now a lab director at Fulgent Diagnostics and a course instructor in Emory’s genetics counseling program, was the lead author.

Wilcox_William_Genetics_22

William Wilcox, MD, PhD

“It took many years and advances in technology to move the molecular definition from localization on the X chromosome to a specific mutation,” Wilcox says.

Still, with current DNA sequencing technology, this kind of investigation and genetic discovery takes place all the time. Why focus on this particular paper or family?

*This gene is a big tent — Mutations in FHL1, the gene that is mutated in the Uruguayan family, are responsible for several types of inherited muscle disorders, which differ depending on the precise mutation. In 2013, an international workshop summarized current knowledge on this family of diseases.

Some forms of FHL1 mutation are more severe, such as reducing body myopathy, which can have early childhood onset leading to respiratory failure. Other forms are less severe. While some men in the Uruguayan family died early from heart disease, the man who Wilcox helped treat is now teaching high school and his hypertrophic cardiomyopathy is stable on a beta blocker.

“Studying a sample of his muscle proved that we had the right gene and some of what the mutation does,” Wilcox says.

*Studying rare mutations can lead to blockbuster drugs – The discovery of potent yet expensive cholesterol-lowering PCSK9 inhibitors, which grew out of the study of familial hypercholesterolemia, is a prominent example.

FHL1 regulates muscle growth by interacting with several other proteins. Probing its function may yield insights with implications for the treatment of muscular dystrophies and possibly for athletes. As NPR’s Jon Hamilton explains, the development of myostatin inhibitors, intended to help people with muscle-wasting diseases, has led to concern about them becoming the next generation of performance-enhancing drugs. Read more

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Metagenomics explainer

A term we heard a bunch at the Emory Microbiome Symposium in November was “metagenomics”. Time for an explainer, with some help from Emory geneticist Tim Read.

Nature Reviews Microbiology defines metagenomics as “genomic analysis of microbial DNA that is extracted directly from communities in environmental samples.”

This technology — genomics on a huge scale — enables a survey of the different microorganisms present in a specific environment, such as water or soil, to be carried out. Metagenomics is also emerging as a tool for clinical diagnosis of infectious diseases.

Read notes that the term specifically refers to “shotgun” sequencing of environmental DNA.

“The shotgun approach is to randomly sample small pieces of the DNA in the tube, no matter which organism they came from,” he says. “The output is a mélange of different genes from bacteria, viruses, fungi, plants and humans.  The data is fascinating but the analysis is daunting.” Read more

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Autoimmune gene link for subtype of juvenile arthritis

Geneticist Sampath Prahalad and the families he works with were part of this recent PNAS paper, which probes genetic risk factors for systemic juvenile idiopathic arthritis.

There are several subtypes of juvenile arthritis, and sJIA (systemic juvenile idiopathic arthritis) sounds especially painful because of its inflammatory symptoms: daily spiking fever and skin rashes in addition to joint pain.

The international team of investigators assembled what they report as the largest collection of sJIA patients (close to 1000) and identified HLA-DRB1*11 as a genetic risk factor for sJIA.

HLA-DRB1 alleles have also been linked to autoimmune diseases such as multiple sclerosis, type I diabetes and (adult) rheumatoid arthritis. The finding strengthens the case for trying existing medications that target T cell activation in sJIA. Read more

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Fragile X regulation is a finely tuned machine

A PNAS paper published Monday demonstrates the kinds of insights that can be gleaned from a large scale sequencing project examining the fragile X gene.

Most children (boys, usually) who have fragile X syndrome have a particular mutation. An expanded “triplet repeat” stretch of DNA, which is outside the protein-coding region of the gene, puts the entire gene to sleep.

At Emory, geneticist Steve Warren, cell biologist Gary Bassell and colleagues have been identifying less common changes in the fragile X gene by looking in boys who are developmentally delayed, but don’t have the triplet repeat expansion. The first author of the paper is former postdoc Joshua Suhl, now at Booz Allen Hamilton in Massachusetts.

The authors describe two half-brothers who have the same genetic variant, which changes how production of the FMRP protein is regulated. These examples show that the fragile X gene is so central to how neurons function that several kinds of genetic glitches in it can make this finely tuned machine break down.

“This is a hot area and not much is known about it,” Warren says. Read more

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