NINDS - National Institute of Neurological Disorders and Stroke Grants

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia, and a major contributor to Alzheimer’s disease (AD), the most common cause of dementia. Noninvasive biomarkers are critical for development of prevention and treatment strategies for VCID. The first grant cycle of the MarkVCID consortium identified 11 candidate imaging and fluid biomarkers. In this second grant cycle (RFA-NS-21-005), the VCID consortium has carried out “comprehensive multi-site clinical validation of up to six of these 11 biomarkers.” Through a strong partnership between Washington University School of Medicine and the University of Texas, Southwestern Medical Center (WU-UTSW), we have enrolled approximately 200 particpants, who have been longitudinally followed with standardized cognitive assessments, MR imaging, and blood collection. This supplement is needed to assay the collected blood samples from these participants to measure plasma neurofilament light chain (NfL) and pTau 217 levels. These blood biomarkers will provide data on neuronaxonal injury and Alzheimer’s disease status, and will be important for future analyses.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract Epilepsy is a severe neurological disease affecting more than 65 million people worldwide and is characterized by unpredictable abnormal electrical discharges resulting in recurrent seizures. About one third of patients with epilepsy suffer from intractable seizures that do not respond to anti-seizure medications (ASMs). Neurosurgical interventions and neurostimulator devices are useful options for only a fraction of patients with drug-refractory seizures, underscoring the urgent need to develop new therapies. One strategy with considerable promise is to engraft new neurons to provide enhanced GABAergic inhibition in an activity-dependent manner. However, use of fetal neurons for cell therapy is associated with practical and ethical issues. Therefore, to overcome such hurdles, in our previous studies, we pioneered the transplantation of human pluripotent stem cell (hPSC)- derived medial ganglionic eminence (MGE)-type human cortical interneurons (cINs) into epileptic mouse brains and demonstrated their integration into dysfunctional circuitry, accompanied by the suppression of seizures and comorbid behavioral abnormalities. Furthermore, more recently, we have determined the optimal stage of human cIN differentiation to ensure maximal integration into host circuitry as well as safety without risk of tumor formation, and developed a method to efficiently generate these safe and highly migratory populations of synchronized early postmitotic cINs from hPSCs in large quantities, bringing cell therapy for epilepsy one step closer to reality. Furthermore, we have successfully tested the efficacy of human early postmitotic cINs in 2 different models of temporal lobe epilepsy (TLE), observing >80% of seizure reduction. With these strong previous studies, now we are ready to embark clinical translation of this novel and restorative therapy for epilepsy patients with limited options. Thus, in this proposed study, we will scale up production of synchronized early postmitotic cINs that are optimal for grafting under cGMP condition. For added safety, we will utilize well- characterized HLA-edited hypoimmunogenic iPSCs to minimize the need for immunosuppression for off-the- shelf use of human cINs. We will also extensively analyze the produced early postmitotic cINs’ phenotype, efficacy, safety, tumorigenesis and biodistribution to seek IND approval. Once we obtain IND approval, we will do a first-in-human clinical trial of early postmitotic cIN grafting with a primary goal of safety analysis, while also checking efficacy as a secondary measure. This will be done in patients with intractable TLE who are candidates for resection while they undergo intracranial EEG to identify the seizure focus without additional invasive steps. Completion of these studies is pivotal for translating this experimental therapy into a viable therapeutic strategy for intractable epilepsy.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract This is an administrative supplement application to the parent grant to support the purchase of a new microscope system due to the unexpected failure of a critical component in our existing system. Due to the age of the existing microscope, manufacturing of the failed parts was discontinued, and newer alternatives are incompatible with the existing system. Attempts to source used parts have proved challenging, and reliance on microscopes in other laboratories or shared facilities have been inadequate, which has delayed our progress on the proposed aims because of limited scope access and other practical limitations detailed in the application. These factors underscore the need for a sustainable solution as our proposed aims rely heavily on high resolution confocal microscopy. This equipment breakdown was entirely unanticipated during grant submission and reporting periods, precluding any rebudgeting from existing funds to adequately address the loss of independent high- resolution imaging capacity. As such, an administrative supplement is requested, with the institution committing matching funds in order to fully cover the cost of the new imaging system. Several imaging systems are considered, and the proposed solution represents the most cost-effective way to restoring full research productivity.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract Support is requested for a Keystone Symposia conference, “Mitochondria Signaling in Physiology and Disease,” organized by Drs. Navdeep S. Chandel and Aleksandra Trifunovic, with scientific programming input from Keystone Symposia. The meeting will take place February 9–12, 2026 at Keystone Resort in Keystone, Colorado. For decades, mitochondria were cast in the limited, yet essential role as powerhouses of the cell. In the past 25 years, this view has changed as mitochondria have emerged as a major signaling hub that dictates cellular fate and function to control cellular physiology. Aberrant mitochondrial signaling can cause diseases, which have historically been attributed to a lack of ATP within cells with mitochondrial dysfunctions. A novel conceptual framework for the role of mitochondria in cellular physiology has emerged, yet the mechanistic details of how mitochondrial signals dictate cell fate and function are not fully understood. While traditional views in the field emphasized impaired ATP production and increased oxidative stress as primary drivers of aging, recent research has highlighted additional mechanisms. These include the role of mitochondria-generated reactive oxygen species (ROS), metabolites, and mitochondrial DNA (mtDNA) as key signaling molecules that regulate inflammation, epigenetic modifications, and cellular stress responses, offering new insights into their contribution to primary mitochondrial diseases, autoimmunity, aging and neurogenerative diseases like Parkinson’s disease. This Keystone Symposia meeting aims to bring together a cross-disciplinary group of biologists, clinicians, and pharmaceutical scientists to broaden our basic understanding of the role of mitochondria as central signaling hubs in the cell, as well as address whether mitochondria can be targeted for a variety of diseases including inflammation and neurodegeneration, thereby reducing the burden of neurological disease. This meeting will support new collaborations geared toward improving disease-focused areas where mitochondria play critical roles. Attendees will also benefit from training workshops, panel discussions and a career roundtable, enhancing their skills and expertise in the field.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary The 2026 Gordon Research Conference (GRC) on Ligand Recognition & Molecular Gating will be held from March 15th-20th at the Renaissance Tuscany Il Ciocco Resort, Italy. The GRC will be preceded by the related Gordon Research Seminar (GRS), which is organized by and for PhD students and postdocs (March 14th-15th). The topic is unique, as it addresses the structures, functional mechanisms and higher-order assemblies of three important classes of transmembrane proteins: ion channels, active transporters, and G- protein coupled receptors (GPCRs). These proteins are central to human physiology and their dysfunction leads to neurological, muscular, endocrine and metabolic diseases, making them therapeutic targets of more than 50% of current drugs. Understanding their isolated and integrated structure and function is essential to enable new opportunities for intervention, which ultimately will improve human health. In recent years the boundaries between the three protein classes have vanished, as we see protein families that comprise transporter, channels and receptors (e.g., ClCs, 7-TM proteins), and proteins that are natural chimera of channels with receptors (e.g., bestrhodopsin), pumps (e.g., K+-ATP-channel), or transporters (e.g., SLC9C1). Therefore, bringing together scientists who work on these three classes of membrane proteins is a timely and necessary endeavor. Originally, this GRC/GRS focused on the molecular mechanisms underlying ligand recognition, substrate translocation, regulation of function, and signal transmission; often addressed through a structural biology approach. However, with the recent breakthroughs in cryogenic electron microscopy it has become quite routine to solve structures of isolated membrane proteins, and thus challenges in the field have shifted. In this edition, we aim to modernize and direct the focus to current frontiers in the field, such as the study of the structure, function and interaction of these proteins with lipids, with partner proteins, in super- complexes, and ultimately in a cellular context. New structural methods such as cryo-electron tomography and native-mass spectrometry of vesicles or cellular compartments combined with computational approaches now allow to acquire an integrated structural characterization of these protein classes, while advanced single- molecule techniques allow to unravel kinetics and energetics avoiding ensemble averaging. The GRC/GRS on Ligand Recognition & Molecular Gating offers the ideal platform for the presentation and discussion of latest, unpublished research results, and formal and informal exchange between scientists at different career stages and from different continents. It will stimulate the establishment of new collaborations and promote enthusiasm for science among young researchers. The program will have about 40 invited speakers, a mix of invited well- established leaders and young investigators in the field, and postdoc and graduate student speakers selected from abstracts. In addition to platform and poster sessions, a “Career Advising” Session as well as a power-hour will foster in-person contact, networking and collegial advice.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Building upon the success of past meetings, the 2026 Gordon Research Conference (GRC) on Thalamocortical Interactions will bring together leading neuroscientists, from early career to established investigators, to discuss the latest breakthroughs in understanding the functions of the nervous system influenced by the thalamus. The scientific sessions will highlight cutting-edge discoveries on thalamus-brain interactions in normal and disease conditions. Session topics will include the role of the thalamus in brain plasticity and stroke recovery, movement, decision-making, development, and visual and tactile sensory processing, as well as topics new to this GRC, such as thalamic contributions to pain and itch processing, conscious states, addiction, and motivation. A major goal of this international conference is to foster interactions among scientists at all career stages, from graduate student and postdoctoral fellows to early career and senior investigators and spanning wide-ranging areas of expertise and interests to brainstorm new hypotheses related to thalamic function and to stimulate new collaborations. Leading researchers in the field will present their most current, unpublished work with extensive discussion planned for each session. Discussion will be further fostered during time set aside for more informal interactions. To promote the next generation of neuroscientists, short talks will be selected from abstracts submitted by graduate students and postdoctoral fellows. In addition, junior faculty represent a third of confirmed invited speakers. Finally, this GRC will be preceded by a Gordon Research Seminar (GRS), organized by graduate students and postdoctoral fellows, which will feature talks and posters by trainees. The GRS will serve as a forum for trainees to present their work and to broaden their peer network and will complement the GRC in bringing together scientists from around the world to discuss and identify new directions in thalamus-brain interactions. The 2026 conference promises to continue the highly regarded tradition and reputation established by the decade-long history of the Thalamocortical Interactions GRC series, bringing top neuroscientists from around the world to communicate innovative science, develop new hypotheses of thalamus function, establish new collaborations among participants, and nurture the next generation of young neuroscientists.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary The purpose of the 7th World Parkinson Congress (WPC 2026) is to address a continued need for worldwide dialogue on the multifaceted problems of Parkinson’s Disease (PD) and to formulate and propose effective solutions, including new approaches to research and better models of care for people with PD (PWP). The WPC 2026, to be held from May 24 – 27, 2026 in Phoenix, Arizona, is the only international meeting in the field of PD that brings the whole PD community together for high-level scientific and lay sessions. Delegates at the meeting represent neuroscientists, physician-researchers, physicians, PWP, care partners, NPs, RNs, PTs, OTs, SLPs, SWs, and more from around 70 countries. The four-day program highlights advancements in the science of PD and models of care for PWP. Allowing researchers (basic, translational and clinical) the opportunity to exchange data on scientific advancements across different areas of science to help them explore and discuss new ideas and build collaborations they might otherwise not have considered. Including junior investigators in this important meeting offers interaction between early-stage and established leaders supporting the next generation of scientists. Inspiring those who are new to the PD field will help them to stay motivated and dedicated to ending PD. Broad support and involvement from the PD community (over 100 partnering organizations from 40 countries) shows that the WPC is the right venue for these multiple stakeholders to meet and build collaborations. Cross-pollination of experts researching and treating PD along with those living with the disease will spur new innovative research, identify potential solutions to unmet needs, and advance therapies for people with PD. More than 60 committee members have designed an elaborate scientific program with 160 speakers from all areas of the PD community with sessions designed to maximize learning potential and dialogue, including large and medium-sized as well as incredibly intimate round-table sessions with just 12 participants discussing a topic in depth. The morning plenaries will look at the Biological definition and staging of PD: Use and Implications for care and research; Current state of the disease- modifying therapy (DMT) pipeline for Parkinson’s disease; and Exercise and PD. Plenaries set the stage for discussion in later sessions covering a wide range of topics such as: Organelle (Dys)function and Crosstalk in PD; Subtypes of PD and their Implications; Research Advances in GBA1- and LRRK2-associated PD; Artificial Intelligence, Big Data, and Digital Devices in PD Care; Immunity and inflammation in PD; The science of boosting physical and cognitive health in PDs; The Gut-Brain Axis in PD; Therapies for Advanced Disease and more. At the end of each day, Controversy sessions bring the delegates together for lively debates. There will be both Scientific and Living with PD posters highlighted in Poster sessions and tours to maximize interaction among the delegates. Authors of the 12 most outstanding posters will be invited to present oral ʻHot Topicsʼ talks to the plenary audience, to further promote scientific dialogue, and foster more collaborations.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Leukodystrophy with vanishing white matter (VWM) is a severe, progressive neurodegenerative disease that most commonly afflicts infants and children. There are no disease modifying treatments. VWM is caused by autosomal recessive mutations in the five subunit genes of the Eukaryotic Initiation Factor 2B (eIF2B) complex, with most mutations occurring in EIF2B5. eIF2B is required for the first steps of protein translation, but also regulates the integrated stress response (ISR). The ISR can be triggered by minor stressors such as viral infection or trauma that decrease eIF2B activity; but in the context of VWM, results in acute and devastating neurological deterioration. Recent work, including ours, has shown abnormal, persistent activation of the ISR in VWM. This is caused by increased expression of stress response genes, such as ATF4, selectively in astrocytes. Concurrent work has shown that VWM astrocytes inhibit oligodendrocyte precursor cells (OPCs) from maturing, leading to decreased production of myelin, the core “vanishing white matter” pathology. Our preliminary data suggests that these two principal features of VWM pathogenesis, deregulated ISR and astrocyte-mediated oligodendrocyte impairment, are associated. However, studies of a therapeutic compound ISR inhibitor (ISRIB) in an EIF2B5-mutant mouse model failed to normalize disease pathologies and showed only partial efficacy. Our goal is to combine scientific insights from an interdisciplinary team of three VWM investigators to develop a targeted and highly translatable therapy for VWM. Due to VWM’s loss of function and monogenic nature, we are investigating adeno-associated virus (AAV) EIF2B5 gene replacement therapy. Advances in AAV vectors have led to safer and more efficient viral vehicles to deliver transgenes, and AAV serotype 9 has become the most widely used for neurological indications. In 2019, AAV9 gene therapy for spinal muscular atrophy achieved FDA approval based on preclinical and clinical work conducted at Nationwide Children’s Hospital, demonstrating the resources and expertise at our disposal to successfully translate a therapy from proof-of-concept to regulatory approval. Our project is to develop and test AAV-mediated transgene rescue of EIF2B5, with the ultimate goal to prevent or mitigate VWM disease. In Aim 1 (R61 phase) we will determine a lead AAV construct by comparing cell-specific and ubiquitous promoters, including a novel astrocyte-specific promoter. We will then ensure translatability of our therapeutic by validating expression and attenuation of disease markers in VWM human patient-derived organoids. Upon selection of a lead candidate, in Aim 2 (R33 phase) we will determine a safe and efficacious dose in two VWM mouse models using clinically relevant outcome measures, including magnetic resonance imaging and electroencephalography. In summary, we detail a rigorous approach to develop and optimize a lead candidate, targeting the underlying astrocytic VWM pathogenesis, and validate it in three models to enhance translation.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY / ABSTRACT The internal representation of space in the mammalian brain is crucial for supporting an animal's ability to navigate complex environments. Grid cells in the medial entorhinal cortex (MEC) are believed to provide a reliable and scalable representation of an animal's position through periodic firing fields arranged in a hexagonal pattern during 2D navigation. Recent experimental findings strongly support continuous attractor network (CAN) models that posit that grid cell activity is constrained to a 2D toroidal manifold which, when anchored to behavior, gives rise to structured firing patterns. However, it remains unresolved how grid cells subserve complex spatial behavior such as 3D navigation, and whether CAN models generalize across species with distinct navigational demands. Prior studies investigating grid cells in flying bats suggested that grid cell spatial responses lacked global structure, contrasting sharply with structured grid cell responses found during 2D navigation in both bats and rodents, However, these studies focused on unstructured navigation driven by human intervention, and were limited to single cell analysis of small neural populations. Spatial representations in bats are known to be modulated by non-positional aspects of behavior as well as the presence of human experimenters. Thus, how grid cells represent the bat’s natural, self-selected flight patterns is not well understood. Furthermore, MEC is intricately connected with the hippocampus, which has been shown to reflect the animal’s action plans. However, whether action plans emerge in MEC during ethological goal-directed navigation remains unexplored. By leveraging the ethological advantages of bats and breakthroughs in wireless Neuropixels recording techniques, this proposal aims to examine how grid cells underlie bats' natural, self-selected flight paths during 3D navigation and connect these findings to existing grid cell models. In Aim 1, I will characterize grid cell spatial responses and population dynamics during 3D navigation to test the hypothesis that grid cells exhibit periodic spatial responses along bats’ natural flight paths and whether grid cell population activity is constrained to a toroidal manifold. In Aim 2, I will investigate non- spatial representations to test the hypothesis that MEC reflects navigational action plans during goal-directed 3D navigation. The proposed work could uncover fundamental mechanisms that are conserved across species and may shed light on how MEC supports spatial memory functions, providing vital insights that could help advance therapeutic approaches for neurological disorders such as Alzheimer's. The proposed fellowship training plan provides a comprehensive training strategy to develop the necessary expertise to carry out this research project in the Yartsev Lab, one of the world’s leading bat neuroscience labs.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary / Abstract The conference, “Planning for Prevention of Parkinson's Disease and Related Synucleinopathies: A trial design forum”, the 4th in this now biennial series, will be held May 22 to 24, 2026, with future conferences planned for 2028 and 2030. The long-term objectives of this R13 program are to foster the education, training, and research of investigators in the emerging translational and clinical neuroscience theme of preventative therapeutics for Parkinson’s disease (PD) and related synucleinopathies like dementia with Lewy bodies (DLB); and to improve the design of the first prevention trials by fostering exchange of early experiences and emerging visions. These objectives will be achieved through five specific aims (SAs). SA #1 is to educate and update attendees on the critical design elements for prevention trials via interactive symposium sessions and workshops. SA #2 is to engage and educate early career investigators (ECIs) through travel fellowships and an additional curriculum with networking and mentorship opportunities, with direct support from this project. SA #3 is to foster partnerships within the growing community of stakeholders in synucleinopathy prevention, including individuals who are at high risk based on genetic and prodromal features and thus most likely to benefit from effective preventative therapy. SA #4 is to facilitate pre-competitive knowledge exchange and collaboration among researchers developing the first prevention efforts by inviting sharing and comparing of their early protocols and designs. SA #5 is to ensure enduring and wide access to the knowledge gained through the open-access publication of meeting findings and consensus in peer-reviewed neuroscience journals. Thuse the conference series will engage, educate, and motivate a wide collaborative community of prevention stakeholders to accelerate development of rigorously designed early trials for PD prevention, thereby enhancing prospects for their success.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY The Gordon Research Conference (GRC) on the Neurobiology of Cognition has been a flagship meeting for this highly interdisciplinary field since its inception in 2010. The 2026 convocation will be the eighth meeting in the series. The long-term goal of the conference is to improve the treatment of cognitive disorders through a better understanding of human cognitive function in health and disease. To this end, the conference has four main goals: To promote discussion and collaboration between scientists working in different domains of cognitive neuroscience; to highlight important recent discoveries and gaps in our knowledge; to encourage intensive discussion of new and unpublished findings that have the potential to change the field; to enhance the career- long growth of scientists in the field, with a particular emphasis on junior scientists and trainees. To achieve these aims, the conference brings together leading experts with early-career scientists and trainees for a weeklong experience characterized by both cutting-edge research presentations and relaxed interactions. Broad topics to be covered include memory, decision-making, perception, action, and social cognition. GRC speakers are encouraged to present and emphasize new results and cutting-edge laboratory techniques. In addition, two sessions on topics of emerging interest are introduced to the itinerary this year: one devoted to the interface of cognitive neuroscience and artificial intelligence, and the other focused on advances in transcranial and intracranial neuromodulation in the context of basic research and clinical treatment. Twenty-nine invited speakers will join approximately 120 additional investigators and trainees for the weeklong conference. The GRC will be preceded by the Gordon Research Seminar (GRS) on the Neurobiology of Cognition, geared toward graduate students and postdoc attendees. The GRC format fosters communication and collaboration by hosting the meeting in a remote location and encouraging all attendees to participate for the entire week. Speakers are invited on the basis of their availability to stay for the entire conference, with exemptions reviewed on a case-by-case basis. The 9 GRC sessions begin with the first session Sunday evening, and two per day Monday through Thursday. Daily meals are held together in a communal dining room, and free time for recreational activities and informal scientific discourse is left open in the afternoon. This meeting structure helps to break down barriers between topic subfields and career ranks, and provides unique networking and mentorship opportunities. The organizers of the GRC and GRS make extensive efforts to select speakers who represent perspectives from across the field. Priority for acceptance to the attend the meeting and for funding support will be given to trainees. Through its 14-year history, the Neurobiology of Cognition GRC has helped to grow this field and has fostered career growth and new collaborations. The chairs of the GRS and GRC expect the 2026 meeting will be another successful rendition of this flagship meeting.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary: Studies of presynaptic physiology at the neuromuscular junction (NMJ) have traditionally relied on the assumption that the probability of release is homogeneous across the hundreds of release sites or active zones at these synapses. However, a growing collection of evidence suggests that the probability of release varies widely across active zones at the NMJ. There is currently no method to quantify the spatial distribution of active transmitter release sites with single vesicle resolution at mammalian NMJs. Therefore, our main objective is to develop and use a new approach to characterize the probability of neurotransmitter release at individual active zones of mouse NMJs by improving upon previous attempts to visualize neurotransmitter release. We propose to investigate heterogeneity in probability of release across the hundreds of mouse active zones at the NMJ in the context of normal physiological and diseased conditions. We aim to demonstrate this using a novel optical probe to resolve neurotransmitter release at the level of a single quantal release event. For this purpose, we developed an optical probe by conjugating an intensity-based acetylcholine sensing fluorescent reporter, iAChSnFR to an scFv antibody fragment directed against nicotinic acetylcholine receptors (mAb35) that does not interfere with the normal functioning of the receptor channel. Frist, we will characterize the probability of transmitter release in healthy mouse NMJs. We will visualize synaptic vesicle release events using our novel acetylcholine receptor-targeted acetylcholine sensor (iAChSnFR-mAb35) in the mouse epitrochleoanconeus muscle and then calculate the probability of neurotransmitter release from each live iAChSnFR-mAb35 transient recorded during synaptic activity by mapping these events onto the localization of presynaptic active zones. Second, we will repeat this approach in the amyotrophic lateral sclerosis (ALS) model mouse NMJ evaluating the impact of disease progression. We hypothesize that the regulation of transmitter release within active zones may be different when comparing healthy and ALS NMJs. The proposed work promises to provide an important new tool for studying the probability of neurotransmitter release and resolving uncertainties in the heterogeneity of individual transmitter release-site function by correlating active zone structure and function under normal physiological conditions and in disease. Such an investigation promises to transform the ways in which we study and understand presynaptic physiology and modulation of neurotransmitter release in healthy and disease states.

NINDS - National Institute of Neurological Disorders and Stroke

ABSTRACT Stroke is the fourth leading cause of disability within the United States. Large vessel occlusion (LVO) subtype of acute ischemic stroke (AIS) is the most devastating among all. Recent pivotal trials demonstrated endovascular thrombectomy (EVT) to be highly beneficial in selected subsets of AIS patients. In the wake of these breakthrough studies, an urgent need exists to assess the benefit of EVT in broader populations that are likely to benefit and determine the limits of this therapy, and to address multiple pressing related issues of management and concomitant therapies, in formal clinical trials. To answer multiple EVT management questions efficiently and concurrently, the NIH StrokeNet National Data Management Center (NDMC) at the Medical University of South Carolina, along with the National Coordinating Center and StrokeNet Thrombectomy Endovascular Platform (STEP) Executive Committee, will develop a robust EVT clinical trial platform within NIH StrokeNet. STEP will be optimized to definitely answer EVT-related questions under an overarching Master Protocol, providing an inferentially integrated framework and shared infrastructure, as a randomized, multi-factorial, Bayesian, adaptive platform trial. The STEP trial team will develop operational cores and scientific advisory groups designed to support three broad categories of trials: expansion of EVT indications, innovative EVT devices and concomitant medical therapies, and novel pre- and early-hospital technologies and systems of care. The foundational STEP Master Protocol will define the largest set of inclusion/exclusion criteria to allow study of all consecutive AIS patients with a visible large or medium intracranial vessel occlusion. It also will outline overall study procedures and terminologies, and the unifying statistical inferential model. As a registry-leveraged trial, STEP will minimize burden on the sites by collecting data using an automated transfer mechanism from existing robust, high-quality national clinical registries. Assessment of distinct interventions will be feasible on the platform concurrently or in tandem, and co-enrollment in multiple interventions and sharing of controls will be allowed to maximize efficiency. Details of a mutually exclusive set of interventions are called Domains. The details of patients eligible for a given domain, details of intervention, rules for randomization and adaptation would subsequently be detailed in domain-specific Appendices to the STEP master protocol. The primary endpoint of the STEP trial is favorable global disability level at 90 days, assessed using utility-weighted analysis of the modified Rankin scale (mRS). The STEP trial will allow most efficient testing of treatment strategies and allow rapid optimization of endovascular treatment landscape and acute stroke care.

NINDS - National Institute of Neurological Disorders and Stroke

Epilepsy is a complex neurological disorder characterized by recurrent, unprovoked seizures affecting around 50 million people worldwide. There are over 30 marketed drugs to treat the symptoms of epilepsy, however, these drugs do not work in nearly a third of the patients leading to drug resistant epilepsy. In addition, there are various forms of genetic epilepsy and rare forms of epilepsy that do not respond to the existing drugs. Nearly 85 genes have been identified in genome wide association studies as causal for childhood and genetic epilepsy such as Dravet syndrome. The SLC1A2 encoding the Excitatory Amino acid transporter 2 or EAAT2 has been noted as a risk gene with at least three mutants in epilepsy patients and animal models have demonstrated that loss of EAAT2 induces neuronal hyperexcitability and recurrent epileptic seizures, while genetic or pharmacological upregulation of EAAT2 reduced epileptic seizures. EAAT2 is a glutamate transporter localized to the astrocytes and responsible for clearing >80% of glutamate from the synapse is downregulated in epilepsy leading to glutamate accumulation and excitotoxicity. In this study, we utilized the hybrid structure-based screening platform to design GTS467, a novel activator of EAAT2 to not only suppress seizures but to promote neuroprotection by restoring normal glutamate neurotransmission. GTS467 has good drug-like properties and high oral bioavailability in plasma and brain tissue was chosen as the lead candidate for in vivo studies at NINDS-epilepsy therapy screening program. GTS467 was tested in various murine models of epilepsy and results from the studies have shown that GTS467 not only reduces seizure burden but can also promote disease modification. In this proposal we aim to further optimize GTS467 (UG3 phase) and in IND enabling studies (UH3 phase) with a goal to deliver a clinical candidate as a disease modifying agent to treat acute and drug-resistant forms of epilepsy which is a significant unmet need.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Stroke commonly disrupts the corticospinal tract (CST) and impairs hand function. Transcranial magnetic stimulation (TMS) interventions that target and strengthen residual CST connections are promising candidates for improving poststroke hand function. To maximize their therapeutic effects, such interventions must repeatedly activate the residual CST and enhance its neural transmission. We and others recently showed in neurotypical adults that resting brain activity spontaneously alternates between EEG activity patterns (brain states) that predict strong and weak CST activation. TMS interventions also preferentially enhance CST transmission when delivered during strong CST states but instead diminish CST transmission when delivered during weak CST states. However, virtually all poststroke TMS interventions are uncoupled from the current brain state, such that only a fraction of TMS stimuli coincide with brain states during which the beneficial effects of TMS are likely to be strongest. To resolve this issue, poststroke TMS interventions should be delivered solely during brain states reflecting strong CST responses. Given that each stroke survivor has a unique pattern of brain damage and recovery-related brain reorganization, these brain states must be fully personalized. We recently developed a personalized machine learning framework that successfully identifies electroencephalography (EEG) activity patterns that predict strong and weak CST states in neurotypical adults. Our framework is fully personalized and is therefore unaffected by lesion-related changes in brain structure and/or function, making it ideal for application in the poststroke brain. In this project, we will use this framework to establish the mechanistic rationale and methodological foundation for future personalized brain state-dependent TMS interventions that target and strengthen the residual CST after stroke. In Aim 1, we will use our machine learning framework to identify personalized brain states that predict strong and weak residual CST activation in chronic stroke survivors; we will also evaluate relationships between our framework’s performance and functional and structural metrics of poststroke CST pathway integrity. Results of Aim 1 will establish poststroke brain state-dependency of residual CST output and the relationship of this state-dependency to CST integrity. In Aim 2, we will develop and validate a real-time EEG algorithm that accurately delivers TMS during personalized brain states reflecting strong and weak CST activation in neurotypical adults. Results from Aim 2 will demonstrate the technical feasibility of personalized, real-time brain state-dependent TMS. Overall, this project fits the scope of the NIMH/NINDS R21 mechanism because it will develop a novel neuroengineering approach that can in the future enhance residual CST transmission and promote paretic hand function in stroke survivors.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT This proposal requests support for partial funding of the 2026 “Barriers of the Central Nervous System (CNS)” GRC and GRS that will be held at Colby Sawyer College, New Hampshire, on June 13-14, 2026 (GRS) and June 14-19, 2026 (GRC). The overall goal of this international conference is to improve understanding of the highly complex cellular and molecular mechanisms regulating the function of the endothelial (e.g., blood-brain barrier (BBB) or neurovascular unit (NVU)) and epithelial (e.g., blood-CSF barrier (BCSFB) and arachnoid) brain barriers in development, maintenance and disease. The 2026 meetings will achieve this goal by covering major aspects of CNS barrier sciences and make a special translational effort to include novel research methodology. Goals include increasing understanding of mechanisms regulating CNS barrier functions, including the blood-brain barrier, blood-spinal cord barrier, blood-retina barrier, neurovascular unit, blood-CSF barrier, in health. This will be coupled with translational efforts to identify novel mechanisms facilitating drug delivery to the brain to treat neurologic diseases. Collectively, these goals are well aligned with NINDS' mission to understand the structure and function of the nervous system and to reduce the burden of neurologic diseases. This interdisciplinary, highly translational knowledge exchange will be fostered by invited talks, daily poster presentations and ample time for non-structured scientific discussions amongst participants. The program will start with a keynote session addressing the selectively permeable nature of the brain barriers. The conference will conclude with a trendsetting keynote session understudied topic of cellular heterogeneity at the CNS barriers. An additional 7 sessions will address: i) CNS barriers in infection and rare diseases, ii) understudied CNS barriers, iii) emerging technologies in CNS barriers, iv) CNS barriers and neuropsychiatric complications, v) CNS barriers across the lifespan, vi) cell-cell communication at the CNS barriers, and, vii) transporters at the CNS barriers. Inclusion of clinicians and industry professionals in the meeting is a critical part of fostering translational discussion, with a particular goal of establishing new collaborations. This application addresses a major public health concern: diseases of the CNS. Instructing young researchers to think of innovative and novel solutions, and to bridge disciplinary interfaces in established laboratories, will advance the capacity to bring new approaches to realize the untapped potential for the treatment of CNS disease.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to determine the potentially pivotal and interactive roles of individual platelet expression of FcγRIIa [SA-1] and wall shear stress (WSS) calculated from patient-specific CT angiography (CTA) computational fluid dynamics (CFD) [SA-2] to explain recurrent ischemia after minor stroke or TIA due to ICAD. A precision model is developed [SA-3] to quantify risk of recurrent ischemic injury, accounting for FcγRIIa, WSS, anti-platelet therapies and platelet reactivity, across a diverse population of stroke and TIA patients with ICAD. Our central hypothesis is that high FcγRIIa plus high shear force pose individual and synergistic risk of stroke recurrence, providing a rational basis for the precision medicine of stroke prevention in ICAD. Our preliminary data reveal that greater platelet FcγRIIa expression identifies patients at greater risk of recurrent cardiovascular events including stroke and that high WSS on CTA CFD predicts recurrent stroke due to ICAD at 1 year. Our three independent specific aims leverage an established research infrastructure and ICAD network of 6 geographically distinct enrolling sites with race-ethnic diverse populations and a longstanding history of productive collaboration to recruit 250 participants with acute cerebral ischemia within 72 hours from symptom onset. The multicenter, observational study will enroll stroke or TIA patients due to 50-99% ICAD diagnosed on routinely acquired CTA and obtain brain MRI and blood sampling for FcγRIIa and platelet assays within 72 hours and again at 1 year after onset. Clinical outcomes will be ascertained at 90 days and at 1 year, with co-registration of serial MRI to quantify interval silent and symptomatic ischemic injury. The Platelet Biology Core at University of Vermont will quantify platelet FcγRIIa expression. The Neurovascular Imaging Research Core at UCLA will conduct central imaging analyses, including CTA CFD quantification of WSS, serial MRI co-registration and imaging adjudication of eligibility and interval endpoints. The Statistical Core will coordinate data management from 6 enrolling sites and the core facilities, conducting predictive statistics, stratification of key biological variables and novel application of clustering analytic strategies to maximally inform a precision model of ICAD stroke risk at 1 year. This timely culmination of synergistic work on shear stress-induced platelet activation in ICAD leverages our robust preliminary data on FcγRIIa, CTA CFD of WSS and precision medicine analytics in stroke, layered on a successful track record of multicenter, observational studies of the most common cause of recurrent stroke. Measurement of individual differences in FcγRIIa and shear stress induced by heterogenous arterial stenoses inform a logical precision medicine strategy to avert stroke. This novel strategy of using diagnostic data easily acquired shortly after stroke or TIA due to ICAD has clear implications for clinical translation via precision medicine enabling individualized stroke treatment, focused on mechanisms of platelet pathophysiology while addressing clinical events and silent, insidious brain damage due to recurrent ischemia distal to the plaque.

NINDS - National Institute of Neurological Disorders and Stroke

SUMMARY: The 2026 Gordon Research Conference (GRC) on Sleep Regulation and Function, themed “Sleep for the Whole Organism,” will mark the seventh installment of this highly successful series. Over the course of the last decade, sleep research has experienced remarkable growth across a variety of disciplines, spanning molecular biology, systems neuroscience, and mental health. Advances in state-of-the-art technologies have enabled significant progress in our understanding of the neurocircuitry underlying non-REM and REM sleep, wakefulness, the roles of neurotransmitters and neuromodulators, genetic contributions to sleep regulation, and the impact of sleep loss on transcriptional and translational dynamics. The 2026 GRC will build on this strong foundation while expanding into new frontiers. The program will explore sleep as a whole-organism behavior, integrating both brain and body perspectives. In addition to core sessions on sleep regulatory mechanisms and emerging findings from non- mammalian species, the conference will highlight recent findings on sleep’s roles in cognition, consciousness, interoception, and waste clearance from the brain. A session will examine the interplay between sleep and post- infectious disease states, reflecting growing interest in how immune challenges—including long-term consequences of viral infections—impact sleep regulation and homeostasis. The program will further emphasize bidirectional brain-body communication, with discussions on the bi-directional interaction between sleep and peripheral physiology, metabolic state, and systemic signals. Finally, the growing interface between artificial intelligence/machine learning (AI/ML) and sleep science will be showcased, illustrating how advanced computational tools are transforming data analysis, predictive modeling, and mechanistic discovery in the field. This GRC will comprise 50 invited speakers and discussion leaders, poster sessions, in the main meeting. It will be preceded by the GRS, which will provide opportunities specifically for graduate students and post-docs. The GRC and GRS will bring together scientists of all career stages in an interactive and safe environment.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Myelinating glial cells play diverse and essential roles in nervous system development and function throughout life. Disruptions to these cells are increasingly recognized in a wide range of neurological conditions, from neurodevelopmental disorders to age-related neurodegenerative diseases. Our understanding of their functions and interactions is rapidly advancing. For instance, myelinating glia are critical in closing periods of heightened plasticity during neural circuit formation. Oligodendrocyte lineage cells also respond dynamically to neuronal activity, enhancing myelination in ways that can be both beneficial and harmful—supporting neural adaptation but also contributing to addiction and facilitating the integration of cancer cells into neural circuits. Promising clinical trials are underway, driven by extensive research into both central and peripheral myelin disorders. Moreover, these glial cells are now implicated in more diseases than previously appreciated, and ongoing studies are likely to yield novel therapeutic strategies. Cutting-edge research is yielding conceptual, mechanistic, and translational insights, and the objective of the 2026 Gordon Research Seminar (GRS: May 23-24, 2026) and Conference (GRC: May 24-29, 2026) on myelin will provide an interactive platform for the community to share their latest findings and develop essential collaborations to advance the field. Taken together the 2026 Myelin GRC, “Myelinating glia and their interactions in health and disease” and the Myelin GRS, “The Leading Edge: Myelinating Glia at the Forefront of Health and Disease” will accomplish this objective by; 1) convening an international meeting of academic, clinical, and industry scientists studying myelinating glial cells in health and disease; 2) discussing exciting new developments by selecting presenters to share unpublished data, with many presentation slots reserved for talks selected from abstracts; 3) promoting collaborative interactions to accelerate conceptual discovery and therapeutic advances; 4) offering trainees as well as established investigators an opportunity to present their work, engage with other scientists, and foster collaboration among participants.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT Protein kinases regulate a wide range of cellular processes by transferring phosphate from ATP to protein substrates (phosphorylation), thereby modulating their function, stability, and interactions. The human kinome consists of over 500 protein kinases, including a subset known as pseudokinases—proteins that adopt a kinase- like fold but lack key catalytic residues. Traditionally, pseudokinases have been considered inactive, functioning primarily as scaffolds or allosteric regulators. However, our laboratory has discovered several pseudokinases that are catalytically active, catalyzing reactions beyond phosphorylation, such as AMPylation, polyglutamylation, and mRNA capping via RNAylation. These findings highlight the catalytic versatility of the kinase fold and suggest that pseudokinases may possess diverse, uncharacterized biochemical activities. This proposal aims to explore the catalytic potential of three rare disease-associated pseudokinases—SCYL1, SCYL2, and TBCK—which have been implicated in neurodevelopmental and neurodegenerative disorders, including autosomal recessive spinocerebellar ataxia-21 (SCAR21/CALFAN), neurogenic arthrogryposis multiplex congenita 4, and TBCK syndrome. Understanding the biochemical and cellular functions of these pseudokinases will provide critical insights into disease mechanisms and uncover new enzymatic activities within this protein class. Thus, we propose to determine whether SCYL1, SCYL2, and TBCK exhibit catalytic activity using a multidisciplinary approach combining biochemistry and mass spectrometry, an approach we have successfully used to uncover catalytic activity in other pseudokinases. We will also assess whether the active site residues of SCYL1, SCYL2, and TBCK are essential for their cellular functions. Using inducible knockdown cell lines, we will evaluate the ability of wild-type and mutant constructs to rescue defects in Golgi morphology, trafficking, and cell proliferation. These studies will clarify the functional importance of the pseudokinase domain and its potential enzymatic activity in cellular processes and disease pathology. The outcomes of this proposal will establish whether SCYL1, SCYL2, and TBCK possess enzymatic activity and determine the functional significance of their active sites in cellular processes. Additionally, the generated tools, including purified proteins and engineered cell lines, will serve as valuable resources for future studies. Ultimately, these results will lay the foundation for an R01 proposal aimed at identifying the physiological substrates of these pseudokinases and elucidating their roles in rare neurological diseases.

NINDS - National Institute of Neurological Disorders and Stroke

Project Abstract The 2026 Synaptic Transmission Gordon Research Conference will bring together an array of scientific leaders and early-career scientists to discuss the latest developments and cutting-edge insights into the synaptic mechanisms that control the nervous system in health and disease. Synapses are the fundamental unit of information transfer in the nervous system underpinning the diversity of information encoding that enables complex adaptive behaviors across species. Dysregulation and degeneration of synapses are central to the pathophysiology of most, neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Therefore, elucidating the molecular and cellular principles governing synaptic biology is essential for understanding brain function and for the development of therapeutics to treat currently incurable brain disorders. This year’s program integrates pioneering research across a broad range of topics, including synapse development, nanoscale organization, signaling, Hebbian plasticity and homeostasis, the synaptic basis of behavior, and how synaptic dysfunction leads to brain disorders. A strong emphasis will be placed on cross-disciplinary dialogue and mechanistic insights, spanning molecular events to circuit-level phenomena throughout the sessions. The long-term goal of the 2026 Synaptic Transmission is to advance mechanistic insight, foster innovation, and bridge basic and translational neuroscience. Specifically, this meeting will focus on elucidating the molecular and cellular mechanisms that govern synapse formation, specificity, and diversity across neural circuits. Secondly, to reveal how synaptic plasticity unfolds across timescales, from milliseconds to years, and how these dynamic processes are integrated to drive learning, memory, and behavior. Finally, we will identify novel pathways for therapeutic intervention.by determining how disruptions in synaptic function contribute to neurodevelopmental, psychiatric, and neurodegenerative diseases, with the aim of translating fundamental discoveries into novel therapeutic strategies that can restore synaptic function and improve outcomes for individuals affected by brain disorders.

NINDS - National Institute of Neurological Disorders and Stroke

Summary: Neuroimaging and histopathology represent two cornerstone methodologies in the study of age-related cognitive impairment and dementia, each offering unique and complementary insights into underlying disease mechanisms and therapeutic strategies. With the advancement of noninvasive imaging techniques aimed at probing the causal pathways and enabling robust early diagnosis of Alzheimer’s disease (AD) and AD–related dementias (ADRD), there is a growing need for postmortem validation studies to confirm the pathological underpinnings of early imaging biomarkers – particularly those related to vascular contributions to cognitive impairment and dementia (VCID). Although postmortem MRI has emerged as a valuable bridge between imaging and pathology, significant technical and methodological challenges persist. This workshop aims to foster the advancement and sharing of cutting-edge technologies, methodologies, and biomedical materials that bridge human neuropathology with neuroimaging research. By capitalizing on rare post-mortem data, the event seeks to deepen our understanding of the pathophysiological processes underlying imaging markers of AD/ADRD. We are requesting funds to support the “Tools and Resources to Understand Pathophysiology with Post-mortem Studies of in vivo Neuroimaging Findings in AD and ADRD” workshop which will take place on August 13-14, 2026, in New York University (NYU) Grossman School of Medicine, New York. The workshop has three specific aims. Aim 1: Bring together thought leaders and experts in the area of post-mortem AD research to advance the field and accelerate the pace of discovery; Aim 2: Foster career development in the field of neuroimaging and neuropathology of age-related dementias, supporting recruitment of new ideas and innovations in this uniquely growing research discipline; and Aim 3: Raise public awareness of and communicate the value of new tools, resources, and biomaterials of neuroimaging and neuropathology research in AD and ADRD to a broader audience. To achieve these aims, the program includes: (i) optimized protocols for postmortem imaging and histopathology; (ii) multidisciplinary topics—including forensic medicine—addressing postmortem interval (PMI) and fixation effects; (iii) daily presentations by Early Career Investigators and trainees selected from abstracts; (iv) new ideas and emerging leaders in VCID research from both in vivo and pathology perspectives at four dedicated panel discussions; (v) hands-on training and demonstrations of advanced tools developed across collaborative sites, including hemisphere imaging, multi- contrast/multi-scale registration, and proteomics; and (vi) shared access to pre- and postmortem MRI data and digital biomaterials for the research community. This unique workshop will serve as a vital forum for idea exchange, fostering new collaborations, and cultivating the next generation of postmortem researchers. Additionally, it aims to advance the translation of ex vivo findings into clinical diagnostics and therapeutic strategies that contribute to the prevention and treatment of Alzheimer’s disease.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT This R13 application is to request support for the 56th Annual Meeting of the American Society for Neurochemistry (ASN) to be held April 18-22, 2026 in St. Charles, Missouri. The total expected attendance for the ASN 2026 meeting is ~500. Past NIH financial support for the ASN meeting has been critical for our goals of enhancing training for future neurochemistry researchers, and for implementing an attractive educational and professional development program. ASN continues to build its scientific program around four interwoven, but distinct, themes to accommodate the breadth of neurochemistry and to provide in-depth analyses of chosen topics: 1) Building the Nervous System, 2) Metabolism and Cell & Molecular Neurobiology, 3) Glial Cell Biology, and 4) Neurodegeneration and Neurodevelopmental Disease. These themes have been selected to increase our understanding of the cellular and molecular basis of neural development and disease. Each theme has one of the four Plenary/Presidential speakers and is represented in varying proportions each year based on the submission of session proposals from the ASN membership and neurochemistry community. ASN is strongly committed to representation at its meetings by scientists at all career levels and from geographical locations throughout the Americas. One of the major goals of ASN is to advance the education and recruitment of early career investigators. The ASN strongly supports these individuals through travel awards, mentorship, and various training workshops. In addition, recent representation of trainees/junior faculty in Symposia and Colloquia has been 40% for Chairs/Co-Chairs and 45% for speakers, demonstrating robust participation of early career investigators. The annual ASN meeting provides participants numerous opportunities to network, collaborate, and exchange ideas. There is also plenty of time for attendees to congregate informally. Multiple activities are planned during the meeting to enhance professional development of early career investigators including 1) career development sessions run by the early career development committee, 2) a student/postdoctoral fellow mingle for networking, 3) lunches with the plenary speakers, 4) participation in Public Forum and High School Day, 5) oral sessions selected from submitted abstracts, with an emphasis on presentations from trainees, 6) two poster sessions for sharing findings and receiving feedback, 7) to defray costs of attendance, travel awards for outstanding early career scientists are available, and 8) a job-posting site and opportunities for trainees to meet with potential future mentors or colleagues. The annual ASN meeting is a one of a kind scientific conference that brings bring together early career and established scientists to experience cutting edge neurochemistry and neurobiology and enhances the careers of early career investigators.

NINDS - National Institute of Neurological Disorders and Stroke

SUMMARY Axonal degeneration of cortical projection neurons underlies several debilitating neurodegenerative disorders including hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis. HSPs are a large heterogeneous group of inherited diseases characterized by length-dependent degeneration of corticospinal motor neuron axons, leading to spasticity and weakness of lower limb muscles. SPG11 and SPG15, two common autosomal recessive forms of HSP, are caused by mutations in the SPG11 and ZFYVE26 that encode spatacsin and spastizin protein, respectively. Spatacsin and spastizin are mediators for autophagy lysosomal reformation that is critical for maintaining lysosome homeostasis. However, how this impairment results in axonal degeneration and how this pathway can be targeted to rescue nerve degeneration in HSP remain unknown. Using patient induced pluripotent stem cell (iPSC)-based models of SPG11 and SPG15, our previous work has identified impaired mitochondrial dynamics in these patient stem cell-derived neurons. We further found aberrant autophagy influx and reduced lysosome transport in these neurons, implying their involvement in HSP. The goal of this proposed study is to dissect the interplays between these pathological processes and to determine their roles in axonal degeneration in HSP neurons. Based on strong preliminary data, we hypothesize that perturbed spatacsin and spastizin result in autophagy lysosomal defects and impaired mitochondrial dynamics, which interact with each other to impair cytoskeleton organization and axonal transport, leading to axonal degeneration in SPG11 and SPG15. This hypothesis will be tested by pursuing the following three aims: 1) to identify the role of spatacsin and spastizin in axonal and autophagy lysosomal defects of patient cortical projection neurons; 2) to determine the interplay between autophagy lysosomal and mitochondrial defects in axonal degeneration of SPG11 and SPG15 cortical neurons; and 3) to rescue axonal degeneration by targeting autophagy lysosomal and mitochondrial defects in vitro and in vivo. By regulating autophagy lysosomal and mitochondrial pathways both genetically and pharmacologically, this study will delineate their roles in axonal degeneration in HSP. The efficacy of targeting these pathways in rescuing axonal defects will be evaluated both in vitro using iPSC models and in vivo using HSP mouse models. Thus, the combination of iPSC model, gene targeting, and HSP animal model in this study provides unique opportunities to identify novel targets and develop potential therapeutics to effectively rescue axonal degeneration in HSP.