Genomics plus human intelligence

The power of gene sequencing to solve puzzles when combined with human Read more

'Master key' microRNA has links to both ASD and schizophrenia

Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few "master keys," risk genes that sit at the center of a network of genes important for brain function. Researchers at Emory and the Chinese Academy of Sciences have created mice partially lacking one of those master keys, called MIR-137, and have used them to identify an angle on potential treatments for ASD. The results were published this Read more

Shape-shifting RNA regulates viral sensor

OAS senses double-stranded RNA: the form that viral genetic material often takes. Its regulator is also Read more

Neuro

Drug discovery: Alzheimer’s and Parkinson’s spurred by same enzyme

Alzheimer’s disease and Parkinson’s disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That’s how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson’s.

Keqiang Ye, PhD

In both Alzheimer’s (AD) and Parkinson’s (PD), a sticky and sometimes toxic protein forms clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies. Here is a thorough review of alpha-synuclein’s role in Parkinson’s disease.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it both more sticky and more toxic. In addition, they have found that AEP similarly processes beta-amyloid, another bad actor in Alzheimer’s, and drugs that inhibit AEP have beneficial effects in Alzheimer’s animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein as it does toward tau.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Ye says. “We reasoned that if AEP cuts Tau, it’s very likely that it will cut alpha-synuclein too.”

A particular chunk of alpha-synuclein produced by AEP’s scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye’s team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can’t cut it is less toxic. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Seeing the nuts and bolts of neurons

Cool photo alert! James Zheng’s lab at Emory is uncommonly good at making photos and movies showing how neurons remodel themselves. They recently published a paper in Journal of Cell Biology showing how dendritic spines, which are small protrusions on neurons, contain concentrated pools of G-actin.

Actin, the main component of cells’ internal skeletons, is a small sturdy protein that can form long strings or filaments. It comes in two forms: F-actin (filamentous) or G-actin (globular). It is not an exaggeration to call F- and G-actin neurons’ “nuts and bolts.”

Think of actin monomers like Lego bricks. They can lock together in regular structures, or they can slosh around in a jumble. If the cell wants to build something, it needs to grab some of that slosh (G-actin) and turn them into filaments. Remodeling involves breaking down the filaments.

At Lab Land’s request, postdoc and lead author Wenliang Lei picked out his favorite photos of neurons, which show F-actin in red and G-actin in green. Zheng’s lab has developed probes that specifically label the F- and G- forms. Where both forms are present, such as in the dendritic spines, an orange or yellow color appears.

Why care about actin and dendritic spines?

*The Journal of Cell Biology paper identified the protein profilin as stabilizing neurons’ pool of G-actin. Profilin is mutated in some cases of ALS (amyotrophic lateral sclerosis), although exactly how the mutations affect actin dynamics is now under investigation.

Read more

Posted on by Quinn Eastman in Neuro Leave a comment

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

Posted on by Quinn Eastman in Neuro Leave a comment

Mitochondrial blindness — Newman’s Emory story

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 (REVERSE and RESCUE) are ongoing.

Despite all the progress, there are still several puzzles connected with mitochondrial diseases affecting vision and particularly Leber’s, the first human disease linked to mitochondrial DNA mutations by Douglas Wallace at Emory in the 1980s.

Newman called Leber’s an “ideal laboratory” for studying mitochondrial diseases of vision, because deterioration of vision in Leber’s tends to happen to one eye first, presenting a window of opportunity to deliver treatment to the other eye. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

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

Posted on by Quinn Eastman in Neuro, Uncategorized Leave a comment

Amyloid vs tau? With this AD target, no need to choose

Keqiang Ye’s lab at Emory recently published a paper in Nature Communications that offers a two for one deal in Alzheimer’s drug discovery.

Periodically we hear suggestions that the amyloid hypothesis, the basis of much research on Alzheimer’s disease, is in trouble. Beta-amyloid is a toxic protein fragment that accumulates in extracellular brain plaques in Alzheimer’s, and genetics for early-onset Alzheimer’s point to a driver role for amyloid too.

In mice, inhibiting AEP hits two targets (amyloid and tau) with one shot

Unfortunately, anti-amyloid agents (either antibodies that sop up beta-amyloid or drugs that steer the body toward making less of it) have not shown clear positive effects in clinical trials.

That may be because the clinical trials started too late or the drugs weren’t dosed/delivered right, but there is a third possibility: modifying amyloid by itself is not enough.

Ye’s lab has been investigating an enzyme called AEP (asparagine endopeptidase), which he provocatively calls “delta secretase.” AEP is involved in processing both amyloid and tau, amyloid’s intracellular tangle-forming counterpart. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

More pieces in Parkinson’s puzzle: VMAT2 and SV2C

The drug target VMAT2 has appeared in biomedical news lately because of a pair of FDA approvals. One medicine treats the iatrogenic movement disorder tardive dyskinesia, the first approved to do so, and the other is for symptoms of Huntington’s disease.

Gary Miller, PhD

When Emory folks see VMAT2, they should think of two things: the neurotransmitter dopamine, and Parkinson’s research conducted by Gary Miller and his colleagues. They have made a case that activators of VMAT2 would be beneficial in Parkinson’s, but the drugs in the news were inhibitors, and presumably would make Parkinson’s worse.

VMAT2 (vesicular monoamine transporter 2) is responsible for transporting dopamine into synaptic vesicles, tiny packages for delivery. As Miller’s lab has shown, mice deficient in VMAT2 can be a model for the non-motor and motor aspects of Parkinson’s. In these mice, not only are certain nervous system functions impaired, but the dopamine packaging problem inflicts damage on the neurons.

Miller’s more recent work on a related molecule called SV2C is puzzling, but intriguing. The gene encoding SV2C had attracted attention because of its connection to the striking ability of cigarette smoking to reduce Parkinson’s risk, possibly mediated by nicotine’s effect on dopamine in the brain.

I say puzzling because SV2C’s role in brain cells can’t be described as easily as VMAT2’s. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Worm collaboration w/Oglethorpe probes neurodegeneration

Emory cell biologist David Katz’s lab has facilitated a collaboration with our neighbors at Oglethorpe University, working with undergraduates on the worm C. elegans and contributing to Alzheimer’s/frontotemporal dementia research. A new article from Oglethorpe describes how C. elegans is ideal for undergraduate biology instruction. Check it out.  

In the photo: Oglethorpe student and Katz lab intern Caitlin May, Oglethorpe biology professor Karen Schmeichel, Elias Castro — also an Oglethorpe student and Katz lab intern, Katz lab postdoc Teresa Lee and David Katz.

Posted on by Quinn Eastman in Neuro Leave a comment

How race + TBI experience affect views of informed consent

The upcoming HBO movie of The Immortal Life of Henrietta Lacks reminds us that biomedical research has a complex legacy, when it comes to informed consent and people of color.

A paper from Emory investigators, published in AJOB Empirical Bioethicstouches on related current issues. The paper examines how race and close experience with traumatic brain injury affect study participants’ views of informed consent in clinical research.

This emerged from a study of community consultation for EFIC (exception from informed consent), in connection with a nationwide clinical trial of progesterone for traumatic brain injury (TBI). EFIC describes clinical research performed when the normal process of obtaining patients’ informed consent is not possible, because of emergency conditions such as seizures or TBI. Before such studies can be undertaken, the FDA calls for protective procedures and community consultation.

In this case, researchers surveyed 2612 people at 12 sites involved in the TBI study. The survey asked about attitudes toward the EFIC aspects of the study and also asked if they had personal experience with traumatic brain injury – either themselves or someone close to them. How that personal connection affected their responses was influenced by race.

Key paragraph from discussion:

Among white participants, increased levels of acceptance of EFIC were found among those with any connections to TBI. On the other hand, among participants identifying as black or other nonwhite races, there was decreased acceptance of EFIC enrollment among TBI patients and no increase in acceptance among those with a family member/loved one with TBI. The fact that black and white participants with no personal TBI experience or with a more distant connection to TBI had similar acceptance rates suggests that baseline acceptance of EFIC among these two groups is fairly similar and that the experience with the condition itself plays a role in driving the observed differences…

Read more

Posted on by Quinn Eastman in Heart, Neuro, Uncategorized Leave a comment

Enhanced verbal abilities in the congenitally blind

A recent paper in Experimental Brain Research from Emory neuroscientist Krish Sathian and colleagues demonstrates that congenitally blind study participants displayed superior verbal, but not spatial abilities, when compared to their sighted counterparts. This may reflect both greater reliance on verbal information, and the recruitment of the visual cortex for verbal tasks.

Sathian’s team has also been investigating, through brain imaging studies, whether the visual cortex is involved in the processing of metaphors (2016 SFN abstract) in the congenitally blind. They previously showed that blind study participants were better at identifying rotated objects by touch. Read more

Posted on by Quinn Eastman in Neuro Leave a comment