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.
Recent work from Drs. Arvind Shukla, Kory Johnson, and Senior Investigator Ed Giniger is 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!
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 Leonardo Cohen and staff scientist 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 Consolidation of human skill linked to waking hippocampo-eocortical replay, 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.
Interested in learning more about COVID research being conducted at NINDS?
Watch the recorded NBC Nightly News interview with Dr. Avindra Nath, NINDS Clinical Director, on NINDS COVID Research. Learn more by reading Dr. Nath and his team's publication, Microvascular Injury in the Brains of Patients with Covid-19, in the New England Journal of Medicine.
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.
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.
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.
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.
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