tACS

TARGETING VAV1 SCAFFOLDING AND ENZYMATIC FUNCTIONS IN MULTIPLE SCLEROSIS VIA BRAIN-PENETRANT MOLECULAR GLUE DEGRADERS

Abstract Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) with significant unmet medical needs, as current therapies offer limited efficacy against neurodegeneration and can have considerable side effects. VAV1, a key signaling protein predominantly expressed in hematopoietic cells, plays a crucial role in T and B lymphocyte activation and is genetically and functionally validated as a therapeutic target in MS. This project proposes an innovative approach to target VAV1 through the development of brain-penetrant molecular glue (MG) degraders. Distinct from Proteolysis Targeting Chimeras (PROTACs) that require a high- affinity ligand for the target protein, molecular glues can mediate degradation by engaging specific protein surface features, such as loops, without the necessity of a dedicated binder. These degraders aim to induce the proteasomal degradation of VAV1, thereby ablating both its enzymatic and scaffolding functions, which are implicated in neuroinflammation. The research strategy involves three primary aims: 1) To optimize lead VAV1 molecular glue degraders for enhanced potency, brain penetration, and favorable pharmacokinetic properties using advanced computational modeling and medicinal chemistry. 2) To evaluate the in vivo efficacy of the optimized VAV1 degraders in preclinical mouse models of MS (Experimental Autoimmune Encephalomyelitis - EAE), assessing their ability to ameliorate disease severity, reduce CNS inflammation and demyelination, and engage VAV1 in the CNS. 3) To investigate the Structure-Activity Relationship (SAR) of a novel non-canonical VAV1 degron motif, aiming to expand the understanding of molecular glue-mediated degradation and enable the rational design of degraders for other challenging therapeutic targets. Successful completion of this project is expected to deliver preclinical candidate VAV1 degraders with the potential for a novel, effective, and safer treatment paradigm for MS. Furthermore, the insights gained into non-canonical degron recognition will significantly advance the field of targeted protein degradation, broadening the scope of "undruggable" targets for therapeutic intervention in various diseases.

A PROTAC Strategy to Combat Botulinum Neurotoxicity

PROJECT SUMMARY/ABSTRACT Botulinum neurotoxin (BoNT), the causative agent of botulism, is the most potent toxin known to humans. While BoNTs are widely recognized for their therapeutic and cosmetic applications, such as Botox™, their increasing use has raised concerns about iatrogenic botulism. Due to their extreme lethality, ease of production, and history of weaponization, the Centers for Disease Control and Prevention (CDC) classifies BoNTs as a Category A bioterrorism threat. Among the seven major serotypes (A-G), BoNT/A, BoNT/B, and BoNT/E account for over 95% of human botulism cases with A being the most prevalent. Despite the severity of botulism, no approved therapeutic exists to rescue intoxicated neurons. The current treatment, a heptavalent antitoxin, can only slow disease progression and requires early administration and prolonged hospitalization due to the inability of antibodies to penetrate infected cells. In the field of small- molecule inhibitors (SMIs), promising scaffolds targeting BoNT/A have been discovered, offering opportunities for further derivatization to incorporate bifunctional approaches. Developing a clinically viable therapeutic requires inhibiting the zinc (Zn2+) metalloprotease light chain (LC) as well as addressing toxin persistence. Through extensive inhibitor screening, we have identified two classes of small molecules that inhibit BoNT/A with submicromolar affinity and demonstrate efficacy in both cellular and animal models. However, the transient nature of these inhibitors necessitates the need of a sustained clearance approach. To achieve this, we propose integrating our previously identified BoNT/A LC SMIs with a targeted protein degradation (TPD) technology for toxin elimination. Based upon the background outlined, vide supra, our research strategy for the ablation of BoNT/A will be focused upon the following three specific objectives: 1) Structural Optimization – Utilize molecular docking, and structure-activity relationship (SAR) analysis to modify inhibitors for TPD ligand attachment. 2) Degrader Design – Development of ubiquitin-protease system (UPS)-based proteolysis-targeting chimeras (PROTACs) and autophagy-targeting chimeras to enhance degradation efficiency. 3) Cellular Evaluation – Assess enzyme inhibition, toxin clearance, degradation kinetics in cells.

Understanding and Enhancing Creative Analogical Reasoning

This talk will focus on our lab's extensive research on understanding and enhancing creative analogical reasoning. I will cover the development of the analogy finding matrix task, evidence for conscious augmentation of creative state during this task, and the real-world implications this ability has for college STEM education. I will also discuss recent research aimed at enhancing performance on this creative analogical reasoning task using both transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS).

How to combine brain stimulation with neuroimaging: "Concurrent tES-fMRI

Transcranial electrical stimulation (tES) techniques, including transcranial alternating and direct current stimulation (tACS and tDCS), are non-invasive brain stimulation technologies increasingly used for modulation of targeted neural and cognitive processes. Integration of tES with human functional magnetic resonance imaging (fMRI) provides a novel avenue in human brain mapping for investigating the neural mechanisms underlying tES. Advances in the field of tES-fMRI can be hampered by the methodological variability between studies that confounds comparability/replicability. To address the technical/methodological details and to propose a new framework for future research, the scientific international network of tES-fMRI (INTF) was founded with two main aims: • To foster scientific exchange between researchers for sharing ideas, exchanging experiences, and publishing consensus articles; • To implement the joint studies through a continuing dialogue with the institutes across the globe. The network organized three international scientific webinars, in which considerable heterogeneities of technical/methodological aspects in studies combining tES with fMRI were discussed along with strategies to help to bridge respective knowledge gaps, and distributes newsletters that are sent regularly to the network members from the Twitter and LinkedIn accounts.

40Hz-transcranial Alternating Current Stimulation (tACS) modulates illusory perception: shedding light on Pareidolia

Neural Nonlinearities Reveal Online Effects of tACS

Optimizing the Montage for Cerebellar Transcranial Alternating Current Stimulation (tACS): a Combined Computational and Experimental Study

Neural nonlinearities reveal online effects of tACS

FENS Forum 2024