Biology subjects

Pleasure, S.

Publications and source records attributed to Pleasure, S..

5 recordsLinked to original sources

bioRxiv2026

Structure-guided design of a targeted autoantibody degrader for neurologic disease

Despite rapid progress in the diagnosis of autoantibody-mediated neurologic diseases, standard-of-care therapeutic options remain limited to nonspecific immunosuppression. Here, we report an alternative therapeutic strategy using targeted protein degradation to eliminate pathogenic autoantibodies while leaving the rest of the immune system intact. We previously discovered autoimmune vitamin B12 central deficiency (ABCD), a neurologic condition in which autoantibodies targeting the transcobalamin receptor (CD320) impair the transport of cobalamin (B12) from the blood into the central nervous system (CNS). Combining scanning alanine mutagenesis by phage display, cryo-electron microscopy, and computational modeling, we elucidated a highly conserved anti-CD320 epitope and defined the structural determinants of antigen-autoantibody binding. Next, we synthesized a lysosome-targeting chimera (LYTAC) comprising the lysosome targeting glycan, triGalNAc, fused to the antigenic epitope of CD320 as autoantibody bait. In vitro, this LYTAC promoted the specific lysosomal internalization and extracellular clearance of anti-CD320, restoring homeostatic cellular uptake of B12. In a passive transfer mouse model of ABCD, LYTAC treatment rapidly cleared anti-CD320 from circulation and prevented penetration of anti-CD320 into the CNS. These findings uncover the mechanism of autoantibody-antigen binding in ABCD and demonstrate targeted autoantibody degradation as a therapeutic strategy that may be generalizable to other autoimmune neurologic diseases.

neuroscience↗

bioRxiv2023

Shh from mossy cells contributes to preventing NSC pool depletion after seizure-induced neurogenesis and in aging

Epileptic seizures induce aberrant neurogenesis from resident neural stem cells (NSCs) in the dentate gyrus of the adult mouse hippocampus, which has been implicated in depletion of the NSC pool and impairment of hippocampal function. However, the mechanisms regulating neurogenesis after seizures remain unknown. Here we demonstrate that Shh from mossy cells is a major source of Shh signaling activity after seizures, by which mossy cells contribute to seizure-induced neurogenesis and maintenance of the NSC pool. Deletion of Shh from mossy cells attenuates seizure-induced neurogenesis. Moreover, in the absence of Shh from mossy cells, NSCs pool are prematurely depleted after seizure-induced proliferation, and NSCs have impaired self-renewal. Likewise, lack of Shh from mossy cells accelerates age-related decline of the NSC pool with accompanying reduction of self-renewal of NSCs outside the context of pathology such as seizures. Together, our findings indicate that Shh from mossy cells is critical to maintain NSCs and to prevent exhaustion from excessive consumption in aging and after seizures.

neuroscience↗

bioRxiv2022

Transient, developmental exposure to patient-derived anti-NMDA receptor autoantibodies causes long-term axonal and behavioral defects

NMDA receptor mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long-term effects of exposure to a patient-derived GluN1-specific monoclonal antibody (mAb) during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced inter-hemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/510196v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@37f452org.highwire.dtl.DTLVardef@1894e46org.highwire.dtl.DTLVardef@171f954org.highwire.dtl.DTLVardef@1a81742_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

NMDA receptors control cortical axonal projections via EPHRIN-B/EPHB signaling

Callosal projections from primary somatosensory cortex (S1) are key for processing somatosensory inputs and integrating sensory-motor information. How the callosal innervation pattern in S1 is formed during early postnatal development is not clear. We found that the normal termination pattern of these callosal projections is disrupted in cortex specific NMDAR mutants. Rather than projecting selectively to the primary/secondary somatosensory cortex (S1/S2) border, axons were uniformly distributed throughout S1. In addition, the density of this projection increased over postnatal life until the mice died by P30. By combining genetic and antibody-mediated loss of function, we demonstrated that it is NR2B-containing NMDA receptors in target S1 that mediate this guidance phenotype, thus playing a central role in interhemispheric connectivity. Furthermore, we found that this function of NMDA receptors in callosal circuit formation is independent of ion channel function and instead depends on interactions with EPHRIN-B/EPHB. Thus, NMDAR cooperates with EPHRIN-B/EPHB in target S1 to control the formation callosal circuits by acting as an accessory axon guidance receptor modulating EPH-dependent repulsion.

neuroscience↗

bioRxiv2019

Combined modulation of SHH and FGF signaling is crucial for maintenance of the neocortical progenitor specification program

Neuronal progenitors in the developing forebrain undergo dynamic competence states to ensure timely generation of specific excitatory and inhibitory neuronal subtypes from distinct neurogenic niches of the dorsal and ventral forebrain, respectively. Here we show evidence of progenitor plasticity when Sonic hedgehog (SHH) signaling is left unmodulated in the embryonic neocortex of the dorsal forebrain. At early stages of corticogenesis, loss of Suppressor of Fused (Sufu), a potent inhibitor of SHH signaling, in neocortical progenitors, altered their transcriptomic landscape. Ectopic activation of SHH signaling occurred, via degradation of Gli3R, resulting in significant upregulation of Fibroblast Growth Factor 15 (FGF15) gene expression. Consequently, activation of FGF signaling, and its downstream effector the MAPK signaling, facilitated expression of genes characteristic of ventral forebrain progenitors. Our studies identify the importance of modulating extrinsic niche signals such as SHH and FGF15 to maintain the competency and specification program of neocortical progenitors throughout corticogenesis. SIGNIFICANCE STATEMENTLow levels of FGF15 control progenitor proliferation and differentiation during neocortical development but little is known on how FGF15 expression is maintained. Our studies identified SHH signaling as a critical activator of FGF15 expression during corticogenesis. We found that Sufu, via Gli3R, ensured low levels of FGF15 was expressed to prevent abnormal specification of neocortical progenitors. These studies advance our knowledge on the molecular mechanisms guiding the generation of specific neocortical neuronal lineages, their implications in neurodevelopmental diseases, and may guide future studies on how progenitor cells may be utilized for brain repair.

developmental biology↗