Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
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alpha-synuclein

The blue spot: where seeds of destruction begin

Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.

The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.

Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons

The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.

“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.” Read more

Posted on July 3, 2018 by Quinn Eastman in Neuro Leave a comment

Tug of war between Parkinson’s protein and growth factors

Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson’s disease (PD), blocks signals from an important brain growth factor, researchers have discovered.

The results were published this week in PNAS.

The finding adds to evidence that alpha-synuclein is a pivot for damage to brain cells in PD, and helps to explain why brain cells that produce the neurotransmitter dopamine are more vulnerable to degeneration.

Alpha-synuclein is a major component of Lewy bodies, the protein clumps that are a pathological sign of PD. Also, duplications of or mutations in the gene encoding alpha-synuclein drive some rare familial cases.

In the current paper, researchers led by Keqiang Ye, PhD demonstrated that alpha-synuclein binds and interferes with TrkB, the receptor for BDNF (brain derived neurotrophic factor). BDNF promotes brain cells’ survival and was known to be deficient in Parkinson’s patients. When applied to neurons, BDNF in turn sends alpha-synuclein away from TrkB.  [Ye’s team has extensively studied the pharmacology of 7,8-dihydroxyflavone, a TrkB agonist.]

A “tug of war” situation thus exists between alpha-synuclein and BDNF, struggling for dominance over TrkB. In cultured neurons and in mice, alpha-synuclein inhibits BDNF’s ability to protect brain cells from neurotoxins that mimic PD-related damage, Ye’s team found. Read more

Posted on September 19, 2017 by Quinn Eastman in Neuro 1 Comment

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 July 12, 2017 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 May 10, 2017 by Quinn Eastman in Neuro Leave a comment

Parkinson’s disease: hold the AMPs

Pathologist Keqiang Ye and colleagues recently published a paper in PNAS that may have implications for Parkinson’s disease pathology and treatment strategies.

The protein alpha-synuclein is a bad actor in PD (nice explainer from Michael J. Fox Foundation); it’s a major constituent of Lewy bodies, the protein clumps that appear in PD patients’ brains, and there is a genetic link too. Alpha-synuclein seems to bring other proteins into the clumps, which may disrupt neuron function.

In particular, it sequesters PIKE-L, an inhibitor of AMP kinase, leading to AMP kinase hyperactivation and cell death. AMP kinase is a metabolic regulator activated by metformin, a common treatment for diabetes. So activating AMP kinase in some situations can be good for your body; however for the neurons affected by alpha-synuclein, activating it too much is bad.

Posted on February 3, 2017 by Quinn Eastman in Neuro Leave a comment