Big data with heart, for psychiatric disorders

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Unlocking schizophrenia biology via genetics

A genetic risk factor for schizophrenia could be a key to unlock the biology of the complex Read more

Brain circuitry linked to social connection and desire to cuddle

Just like humans, prairie voles are capable of consistently forming social bonds with mating partners, a rare trait in the animal Read more

Huntington’s disease

Gene editing reverses Huntington’s in mouse model

Disrupting a problematic gene in brain cells can reverse Huntington’s disease pathology and motor symptoms in a mouse model of the inherited neurological disorder, Emory scientists report.

The researchers used CRISPR/Cas9 gene editing, delivered by a viral vector, to snip part of a gene producing toxic protein aggregates in the brains of 9-month old mice. Weeks later, where the vector was applied, aggregated proteins had almost disappeared. In addition, the motor abilities of the mice had improved, although not to the level of control mice.

The results were published June 19, 2017 in Journal of Clinical InvestigationEncouraging Tweet from Scripps MD/author Eric Topol.

The findings open up an avenue for treating Huntington’s as well as other inherited neurodegenerative diseases, although more testing of safety and long-term effects is needed, says senior author Xiao-Jiang Li, MD, PhD, distinguished professor of human genetics at Emory University School of Medicine.

Huntington’s disease is caused by a gene encoding a toxic protein (mutant huntingtin or mHTT) that causes brain cells to die. Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline.

Touted widely for its potential, CRISPR/Cas9 gene editing has not been used to treat any neurodegenerative disease in humans. Several concerns need to be addressed before its use, such as effective delivery and the safety of tinkering with DNA in brain cells. A similar approach, but using a different technology (zinc finger nucleases), was reported for Huntington’s disease in 2012.  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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Silence away, HD investigators!

Adult mice don’t need the gene that, when mutated in humans, causes the inherited neurodegenerative disorder Huntington’s disease. The finding suggests that treatment strategies for Huntington’s that aim to shut off the huntingtin gene in adults — now in early clinical stages — could be safe.

The results were published Monday, March 7 in PNAS.

How HD gene silencing is supposed to work. The Emory study didn’t test this approach directly, but the Emory study has implications for what types of side effects HD gene silencing may have in humans. Image from HDBuzz.net via Creative Commons.

Huntington’s disease is caused by a gene encoding a toxic protein (mutant huntingtin) that causes brain cells to die. Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline. A juvenile form of Huntington’s disease also can appear during the teenage years.

Researchers led by Xiao-Jiang Li, MD, PhD and Shihua Li, MD, at Emory University School of Medicine, used genetically engineered mice in which the huntingtin gene can be deleted, triggered only when the mice are given the drug tamoxifen. Note: these mice don’t produce toxic mutant huntingtin protein.

When the huntingtin gene is deleted at an age older than four months, these mice appeared to stay healthy, despite having lost their huntingtin genes in cells all over their bodies. They maintained their body weight and could complete tests of movement and grip strength as well as control mice. In contrast with adults, engineered mice younger than four months old whose huntingtin gene was deleted developed lethal pancreatitis.

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Insight into broken record genetic diseases

Those of us who are old enough to remember vinyl records will recall how a scratch can cause the same sounds to repeat many times. A similar type of genetic glitch causes neurodegenerative diseases such as Huntington’s and several forms of spinocerebellar ataxia.

Huntington’s and the spinocerebellar ataxias are known as “polyglutamine” diseases. In each, the affected gene has a stretch where the same three DNA letters are repeated several times — more than usual. As a result, the protein encoded by the affected gene has a patch, where only the building block glutamine can be found, disrupting that protein’s usual functions in the body.

Geneticist Xiao-Jiang Li and colleagues recently published a paper in Cell Reports that may explain why more aggressive juvenile-onset forms of polyglutamine diseases have different symptoms and pathology. Read more

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Aging brains still need “chaperone” proteins

The word “chaperone” refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.

Researchers at Emory University School of Medicine led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhD have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.

The researchers were studying a model of spinocerebellar ataxia, but the findings have implications for understanding other diseases, such as Alzheimer’s, Parkinson’s and Ray Ban outlet Huntington’s. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.

The results were published recently in the journal Neuron. Read more

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Reading the blood: metabolomics

In the Star Trek series, Dr. McCoy could often instantly diagnose someone’s condition with the aid of his tricorder. Medicine on 21st century Earth has not advanced quite this far, but scientists’ ideas of how to use “metabolomics” are heading in this direction.

What is metabolomics? Just as genomics means reading the DNA in a person or organism, and assessing it and comparing it to others, metabolomics takes the same approach to all the substances produced as part of the body’s metabolism: watching what happens to food, drugs and chemicals we are exposed to in the environment.

This means dealing with a huge amount of information. Human genomes may be billions of letters (base pairs) in length, but at least there are only four choices of letter!

A recent article in Chemical & Engineering News explores this concept of the “exposome” and quotes Dean Jones. He and his colleagues recently described how they can use sophisticated analytical techniques to resolve thousands of substances in human plasma. Jones is the director of the Clinical Biomarkers Laboratory at Emory University School of Medicine. The paper is in the journal Analyst, published by the Royal Society of Chemistry.

Analytical techniques can discern more than 2500 metabolites from human plasma within 10 minutes

Using a drop of blood, within ten minutes the researchers can discern more than 2,500 substances in a reproducible way. One fascinating tidbit: when they compared the metabolic profiles for four healthy individuals, most of the “peaks” were common between individuals but 10 percent were unique.

The potential uses for this type of technology are staggering.

Jones reports he has been working with researchers at Yerkes National Primate Research Center to discern early signs of neurodegeneration in transgenic monkeys with Huntington’s disease. He has been collaborating with clinical nutrition specialist Tom Ziegler to examine how diet interacts with oxidative stress, and with lung biology to identify markers for fetal alcohol exposure in animal models.

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