Dr. Avindra Nath Investigates the Mysterious Ways Viruses Affect the Nervous System and is Featured on Global Documentary
The COVID-19 pandemic was not Avindra “Avi” Nath’s first face-off with an enigmatic, rapidly spreading virus. From the AIDS pandemic to the current pandemic, Dr. Nath is one of the world’s foremost experts on how viruses affect the brain. As the NINDS Clinical Director and the head of the Section of Infections of the Nervous System, he occupies a unique niche that requires expertise in two seemingly unrelated fields. “If you’re trained as a neuroscientist or neurologist, you understand the functions of the brain, but if you’re trained as a virologist, you study viruses, and there’s no way you would get exposed to the intricacies of the brain,” Dr. Nath explains. “I trained in both, so I was able to marry the two together.” Read more.
Dr. Nath was also featured on Here’s What We Know About COVID-19’s Impact on the Brain – a documentary produced by Science Magazine that focuses on the impact of COVID-19 in the brain, as well as novel therapeutic approaches to improve the symptoms of long COVID, such as autonomic rehabilitation, and an immune modulating drug trial awaiting regulatory approval. Renown scientists, like Dr. Nath, hope that the knowledge gained from long COVID will benefit those facing post-viral illnesses. You can watch the video in its entirety on YouTube.
Sensory hair cells of the inner ear required for hearing and balance rely on the mechanoelectrical transduction (MET) channel complex to convey mechanical signals from sound or head movements into electrical impulses. Transmembrane-like channel 1 and 2 (TMC1 and TMC2) are thought to form the ion conduction pore of the MET channel, yet the distinctive roles of the two proteins and how TMC1 mutations cause hair cell death remain elusive.
In this article published in BioRxiv, Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing, Drs. Angela Ballesteros and Kenton Swartz discover that TMC1 controls membrane homeostasis initiated by inhibition of MET channels and that deafness-causing mutations in TMC1 lead to constitutive phosphatidylserine externalization that correlates with the deafness phenotype, suggesting that the mechanisms of TMC1-related hearing loss may involve alterations in membrane homeostasis. Read more.
A study published in Cell Reports, led by Dr. Kunwei Wu and team from Dr. Wei Lu’s lab found the differential modulation of tonic inhibition by NMDA receptor subtypes and reveal distinct roles of GluN2A- and GluN2B-NMDA receptors in regulating ɑ5-GABAAA receptor trafficking, tonic inhibition and its homeostatic plasticity in hippocampal neurons. They also demonstrate the regulation of tonic inhibition by NMDA receptors in a kainate-induced seizure model. As dysregulation of tonic inhibition has been shown to be a mechanism underlying a number of pathological brain states, these findings provide insight into crosstalk between glutamatergic and GABAergic systems, as well as how dysregulation of this crosstalk could be involved in epileptic conditions. Read the full publication.
NIH study identifies possible target for certain neurodegenerative disorders. Neurons require mechanisms to maintain ATP homeostasis in axons, which are highly vulnerable to bioenergetic failure. Recent work from Dr. Zu-Hang Sheng and his team offers insights that advance our understanding of axonal energy metabolism; energy deficits are associated with a wide range of neurological disorders. Read full press release.
Adenosine A2A Receptor Activation Enhances Blood–Tumor Barrier Permeability in a Rodent Glioma Model
In a study by Dr. Sadhana Jackson and colleagues published in AACR Molecular Cancer Research, researchers characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. Collectively, these findings demonstrate regadenoson's ability to induce brain endothelial structural changes among malignant glioma cells to increase BTB permeability. Read more.
Scientists Discover a New Molecular Pathway Shared by two Neurodegenerative Disorders
Finding provides a possible therapeutic target for ALS and FTD. Researchers from two independent research teams have discovered how the mislocalization of a protein, known as TDP-43, alters the genetic instructions for UNC13A, providing a possible therapeutic target that could also have implications in treating amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other forms of dementia. Read press release.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder that results in loss of voluntary muscle strength and movement. ALS usually affects middle-aged adults and progresses rapidly, but in the recent study Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis, published in Nature Medicine, an international team reported a new and unique, rare form of ALS with onset in young children followed by a somewhat slower but equally progressive course.
Identifying this new form of ALS was just the start towards a deeper understanding of the mechanisms driving the disease. Read the full NINDS press release, NIH Record article, and see international press coverage of this study.
Drs. Arvind Shukla, Kory Johnson, and Senior Investigator Ed Giniger are changing how we understand the role of genes and the microbiome in aging. Published in iScience, Common features of aging fail to occur in Drosophila raised without a bacterial microbiome reports on unexpected differences in gene expression between flies raised under normal conditions or in the absence of bacteria (with antibiotics). A large body of research has identified many genes that change their expression as an animal ages, and these genes are considered hallmarks of the aging process. In this study, however, the team found that 70% of these classic age-related genes did not change their expression over time when the flies were raised without bacteria, indicating that these genes are actually responding to the microbe-rich environment, rather than the animal's internal aging clock. Read the full NINDS press release, or see the buzz around the story on twitter!
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Researchers at the NNINDS led by Dr. Dorian McGavern have found a possible explanation for why some patients recover much more poorly from brain injury if they later become infected. The findings were published in Nature Immunology. Making use of a mouse model for mild TBI (mTBI) that they had developed previously, the team of researchers discovered that viral, fungal, or a mimic for bacterial infections all impacted blood vessel repair within the meninges. When they looked closer, they observed that some cells of the immune system no longer moved into the site of the injury, which occurred in the uninfected animals, suggesting they were responding to systemic infection. Read press release.
Investigators build a cellular blueprint of multiple sclerosis (MS) lesions providing a better understanding of the entire network of cells. Danny Reich and his team had a fascinating paper recently published in Nature, A lymphocyte–microglia–astrocyte Axis in Chronic Active Multiple Sclerosis. Chronic lesions with inflamed rims, or “smoldering” plaques, in the brains of people with MS have been linked to more aggressive and disabling forms of the disease. Using brain tissue from humans, Dr. Reich and colleagues built a detailed cellular map of chronic MS lesions, identifying genes that play a critical role in lesion repair and revealing potential new therapeutic targets for progressive MS. Read the full press release.
A NINDS team led by Senior Investigator Dr. Leonardo Cohen and staff scientist Dr. Ethan Buch recently published a study mapping out the brain activity that occurs when we learn a new skill and discovered why taking short breaks from practice is a key to learning. In a recent publication appearing in Cell Reports, the researchers used magnetoencephalography to record the brain waves of volunteers as they practiced rapidly typing a code and during short rests between practice. A machine learning approach allowed them to decipher the brain wave activity associated with typing a code. During rests between periods of practice, the brains of healthy volunteers rapidly and repeatedly replayed much faster, compressed versions of the brain waves that occurred during active typing practice. The more a volunteer's brain replayed the pattern during rest, the better they performed during subsequent practice sessions, suggesting rest strengthened the memory of the typing skill.
The study also identified the brain regions where this replay occurs. The researchers hope that the study sheds light not only on the role that rest can play in normal skill learning, but also points to strategies for enhancing skill learning, including as part of rehabilitation interventions after brain injury. Read the full press release, or listen to a short interview with Drs. Cohen and Buch that appeared in the Scientific American.
Distinguishing Type II Focal Cortical Dysplasias from Normal Cortex: A Novel Normative Modeling Approach
Seizure outcomes in epilepsy surgery are better when epileptogenic lesions are identified. There is no widely available automated method for aiding with detection of subtle focal cortical dysplasia lesions. In this study, the researchers describe a novel approach for aiding with detection of these lesions using structural MRI. Detection of subtle dysplastic lesions in individual patients undergoing epilepsy surgery has the ability to significantly improve seizure outcomes in these patients. Read more.
Genome Sequencing Analysis Identifies New Loci Associated with Lewy Body Dementia and Provides Insights into its Genetic Architecture
Led by Dr. Scholz, a team of investigators identified novel risk loci associated with this devastating disease, and they were able to show molecular relationships between Lewy body disease (LBD), Parkinson’s disease, and Alzheimer’s disease. The genome data described in this study constitute the largest sequencing effort in LBD to date and are designed to accelerate the pace of discovery in dementia research. Read more.
An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking
In a project led by Dr. Marta Mota Vieira, we characterized a novel CaMKIIα phosphorylation site, S1459, in the GluN2A subunit of NMDA receptors. Phosphorylation of this residue promotes trafficking of the receptor to the neuronal surface, modulates receptor interactions with trafficking and scaffold proteins. This provides a previously unappreciated link between GluN2A-specific NMDA receptor function and the important synaptic signaling kinase CaMKIIα. Importantly, we found that an epilepsy-associated variant (S1459G) identified at the same residue decreases synaptic expression of NMDA receptors, spine density, and spontaneous post-synaptic currents, consistent with the epilepsy-related variant being a loss-of-function mutation. Read more.
Evidence for a Stereoselective Mechanism for Bitopic Activity by Extended-Length Antagonists of the D3 Dopamine Receptor
Investigators performed a high-throughput screen of a small molecule library to identify a D3R-selective agonist with low cross-reactivity with the closely related D2R. We then conducted a comprehensive structure–activity relationship investigation using iterative medicinal chemistry to establish the structural determinants for potency, efficacy, and selectivity of the agonist at the D3R. An optimized lead compound, ML417, was identified that promotes potent and selective D3R activation. ML417 shows almost no cross reactivity with other receptors, indicating it is globally selective for the D3R. They also identified amino acid residues in the D3R DAR that uniquely interact with ML417, explaining the compound’s unprecedented selectivity. In follow-up studies, ML417 was found to exhibit neuroprotection against toxin-induced neurodegeneration of dopaminergic neurons. Read more.