Nogo Receptor Antagonist LOTUS Promotes Neurite Outgrowth through Its Interaction with Teneurin-4.

Neurite outgrowth is a crucial process for organizing neuronal circuits in neuronal development and regeneration after injury. Regenerative failure in the adult mammalian central nervous system (CNS) is attributed to axonal growth inhibitors such as the Nogo protein that commonly binds to Nogo receptor-1 (NgR1). We previously reported that lateral olfactory tract usher substance (LOTUS) functions as an endogenous antagonist for NgR1 in forming neuronal circuits in the developing brain and improving axonal regeneration in the adult injured CNS.

Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice.

Nogo-Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice.

LOTUS suppresses amyloid β-induced dendritic spine elimination through the blockade of amyloid β binding to PirB.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aβ) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aβ and Aβ-PirB molecular interactions that cause synapse elimination and synaptic dysfunction.

Brain-derived neurotrophic factor (BDNF) induces antagonistic action to Nogo signaling by the upregulation of lateral olfactory tract usher substance (LOTUS) expression.

Neurons in the central nervous system (CNS) have limited capacity for axonal regeneration after trauma and neurological disorders due to an endogenous nonpermissive environment for axon regrowth in the CNS. Lateral olfactory tract usher substance (LOTUS) contributes to axonal tract formation in the developing brain and axonal regeneration in the adult brain as an endogenous Nogo receptor-1 (NgR1) antagonist. However, how LOTUS expression is regulated remains unclarified.

LOTUS overexpression via ex vivo gene transduction further promotes recovery of motor function following human iPSC-NS/PC transplantation for contusive spinal cord injury.

Functional recovery is still limited mainly due to several mechanisms, such as the activation of Nogo receptor-1 (NgR1) signaling, when human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PC) are transplanted for subacute spinal cord injury (SCI). We previously reported the neuroprotective and regenerative benefits of overexpression of lateral olfactory tract usher substance (LOTUS), an endogenous NgR1 antagonist, in the injured spinal cord using transgenic mice. Here, we evaluate the effects of lentiviral transduction of LOTUS gene into hiPSC-NS/PCs before transplantation in a mouse model of subacute SCI.

LOTUS, an endogenous Nogo receptor antagonist, is involved in synapse and memory formation.

The Nogo signal is involved in impairment of memory formation. We previously reported the lateral olfactory tract usher substance (LOTUS) as an endogenous antagonist of the Nogo receptor 1 that mediates the inhibition of axon growth and synapse formation. Moreover, we found that LOTUS plays an essential role in neural circuit formation and nerve regeneration.

Nogo receptor antagonist LOTUS exerts suppression on axonal growth-inhibiting receptor PIR-B.

Damaged axons in the adult mammalian central nervous system have a restricted regenerative capacity mainly because of Nogo protein, which is a major myelin-associated axonal growth inhibitor with binding to both receptors of Nogo receptor-1 (NgR1) and paired immunoglobulin-like receptor (PIR)-B. Lateral olfactory tract usher substance (LOTUS) exerts complete suppression of NgR1-mediated axonal growth inhibition by antagonizing NgR1. However, the regulation of PIR-B functions in neurons remains unknown.

LOTUS as an endogenous protein converting the adult central nervous system environment from nonpermissive to permissive for axonal regrowth after brain injury.

Central nervous system (CNS) injury, such as spinal cord injury (SCI), results in severe sensory and motor deficits due to the poor regenerative capacity of the adult CNS primarily caused by a damaged CNS environment containing a large amount of axonal growth inhibitors, such as Nogo receptor-1 (NgR1), which inhibits axonal regrowth strongly after SCI, and its five ligands. Lateral olfactory tract usher substance (LOTUS), identified in the developing brain, completely antagonizes NgR1 function, promoting neuronal regeneration and functional recovery after SCI. Therefore, we hypothesized that LOTUS might be a useful natural agent for the clinical treatment of SCI in order to increase functional recovery by converting the CNS environment from nonpermissive to permissive for neuronal regeneration.

Axonal regeneration and functional recovery driven by endogenous Nogo receptor antagonist LOTUS in a rat model of unilateral pyramidotomy.

The adult mammalian central nervous system (CNS) rarely recovers from injury. Myelin fragments contain axonal growth inhibitors that limit axonal regeneration, thus playing a major role in determining neural recovery. Nogo receptor-1 (NgR1) and its ligands are among the inhibitors that limit axonal regeneration.

LOTUS Inhibits Neuronal Apoptosis and Promotes Tract Regeneration in Contusive Spinal Cord Injury Model Mice.

Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice.

The soluble form of LOTUS inhibits Nogo receptor type 1-mediated signaling induced by B lymphocyte stimulator and chondroitin sulfate proteoglycans.

There are global efforts in developing therapeutic strategies for central nervous system (CNS) injuries using multimodal approaches. Nogo receptor type 1 (NgR1) has been known as a primary molecule limiting neuronal regeneration in the adult CNS. We identified lateral olfactory tract usher substance (LOTUS) as an endogenous NgR1 antagonist.

Cerebrospinal fluid level of Nogo receptor 1 antagonist lateral olfactory tract usher substance (LOTUS) correlates inversely with the extent of neuroinflammation.

Background: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity.

The Soluble Form of LOTUS inhibits Nogo Receptor-Mediated Signaling by Interfering with the Interaction Between Nogo Receptor Type 1 and p75 Neurotrophin Receptor.

Nogo receptor type 1 (NgR1) is known to inhibit neuronal regeneration in the CNS. Previously, we have shown that lateral olfactory tract usher substance (LOTUS) interacts with NgR1 and inhibits its function by blocking its ligand binding. Therefore, LOTUS is expected to have therapeutic potential for the promotion of neuronal regeneration.

Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS.

Axonal regeneration in the adult mammalian central nervous system is limited in part by the non-permissive environment, including axonal growth inhibitors such as the Nogo-A protein. How the functions of these inhibitors can be blocked remains unclear. Here, we examined the role of LOTUS, an endogenous Nogo receptor antagonist, in promoting functional recovery and neural repair after spinal cord injury (SCI), as well as axonal regeneration after optic nerve crush.

LOTUS overexpression accelerates neuronal plasticity after focal brain ischemia in mice.

Nogo receptor-1 (NgR1) and its ligands inhibit neuronal plasticity and limit functional recovery after brain damage such as ischemic stroke. We have previously shown that lateral olfactory tract usher substance (LOTUS) antagonizes NgR1-mediated signaling. Here, we investigated whether LOTUS enhances neuronal plasticity and functional recovery after brain focal ischemia in adult mice.

Blockade of chondroitin sulfate proteoglycans-induced axonal growth inhibition by LOTUS.

Chondroitin sulfate proteoglycans (CSPGs) are axon growth inhibitors in the glial scar, and restrict axon regeneration following damage to the adult mammalian central nervous system. CSPGs have recently been identified as functional ligands for Nogo receptor-1 (NgR1), which is the common receptor for Nogo proteins, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp) and B lymphocyte stimulator (BLyS). We have previously reported that through its binding to NgR1, lateral olfactory tract usher substance (LOTUS) suppresses Nogo, MAG, OMgp, and BLyS-induced axon growth inhibition.

Axonal branching in lateral olfactory tract is promoted by Nogo signaling.

Mitral cells are major projection neurons of the olfactory bulb (OB) that form an axonal bundle known as the lateral olfactory tract (LOT). After axonal bundle formation, collateral branches sprout from primary axons of the LOT. Recently, we identified LOT usher substance (LOTUS) as an endogenous Nogo receptor-1 (NgR1) antagonist and demonstrated that LOTUS contributes to the formation of the LOT axonal bundle.

Micro-CALI to Study Localized Roles of the Semaphorin Signaling Component CRMP in Axon Growth.

Elucidating the local function of proteins is essential for understanding not only the individual proteins but also the organization of the cell or even tissue as a whole. However, until now, few attempts have been made to understand local proteins function in cells because of a lack of acute inactivation technique of local proteins with high versatility. Here we describe the application of the chromophore-assisted light inactivation (CALI) method to elucidate the role of the semaphorin signaling component CRMP located within the growth cone area in axon growth and growth cone turning.

Sex-Specific Protection of Osteoarthritis by Deleting Cartilage Acid Protein 1.

Cartilage acidic protein 1 (CRTAC1) was recently identified as an elevated protein in the synovial fluid of patients with osteoarthritis (OA) by a proteomic analysis. This gene is also upregulated in both human and mouse OA by transcriptomic analysis. The objective of this study was to characterize the expression and function of CRTAC1 in OA.

[Axonal Regeneration-related Molecules as Biomarkers for Multiple Sclerosis].

Abnormalities in both the nervous and immune systems are thought to be relevant to the pathogenesis of multiple sclerosis (MS). Several functional molecules closely related to axonal regeneration play an important role in not only the nervous system, but also the immune system. Many recent studies revealed that these molecules are associated with the neurological and immunological aspects of the pathogenesis of MS.

Crmp4 deletion promotes recovery from spinal cord injury by neuroprotection and limited scar formation.

Axonal outgrowth inhibitors and scar formation are two major obstacles to central nervous system (CNS) repair. No target molecule that regulates both axonal growth and scarring has been identified. Here we identified collapsin response mediator protein 4 (CRMP4), a common mediator of inhibitory signals after neural injury, as a crucial factor that contributes to both axonal growth inhibition and scarring after spinal cord injury (SCI).

Association of cerebrospinal fluid levels of lateral olfactory tract usher substance (LOTUS) with disease activity in multiple sclerosis.

Importance: Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS.

Objective: To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course.