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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