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Multiple sclerosis is among the most common causes of neurological disabilities in young adults. Over the past decade, several therapeutic strategies have emerged as having potential neuroprotective and neuroregenerative properties. We investigated the effect of intranasal administration of LINGO-1-directed siRNA-loaded chitosan nanoparticles on demyelination and remyelination processes in a rat model of demyelination. Adult male Wistar rats were randomly assigned to one of 6 groups (n = 10 each) and subjected to intrapontine stereotaxic injection of ethidium bromide (EB) to induce demyelination. EB-treated rats were either left untreated or received intranasal LINGO-1-directed siRNA-chitosan nanoparticles from day 1 to day 7 (demyelination group) or from day 7 to day 21 (remyelination group) after EB injection. Chitosan nanoparticle (50 μl) was given alone after EB stereotaxic injection for both demyelination and remyelination groups. Two additional groups received 10 μl of saline by stereotaxic injection, followed by intranasal saline as controls for demyelination and remyelination groups (n = 10/group). Behavioural testing was conducted for all rats, as well as terminal biochemical assays and pathological examination of pontine tissues were done. After EB injection, rats had compromised motor performance and coordination. Pathological evidence of demyelination was observed in pontine tissue and higher levels of caspase-3 activity were detected compared to control rats. With LINGO-1-directed siRNA-chitosan nanoparticle treatment, animals performed better than controls. Remyelination-treated group showed better motor performance than demyelination group. LINGO-1 downregulation was associated with signs of repair in histopathological sections, higher expression of pontine myelin basic protein (MBP) mRNA and protein and lower levels of caspase-3 activity indicating neuroprotection and remyelination enhancement. Show less

Organophosphates insecticides (OPs) are common surface water contaminants in both urban and agricultural landscapes. Neurobehavioral effects on larval fish are known to occur at concentrations higher than those reported in the environment. The aim of this study was to perform a comparative analysis of neurobehavioral, molecular, and biochemical responses of four OPs (diazinon, dichlorvos, malathion, methyl-parathion) via the following endpoint measurements: distance traveled, velocity, gene expression (AChE, c-Fos, LINGO-1B, GRIN-1B), enzymatic acetylcholinesterase (AChE) activity, and carboxylesterase (CES) activity. OP exposures (5 hpf - 120 dpf) on embryo-larval zebrafish (Danio rerio) were assessed using a larval zebrafish behavior assay at concentrations: 0.01, 0.1, 10, and 100 μg/L. Individual OPs had varying degrees of neurotoxicity. Significant hypoactivity was observed in the 100 μg/L treatments for diazinon and malathion (p < 0.05) as compared to the controls. Diazinon-exposed larvae exhibited a 26% locomotor decrease, and hypoactivity was observed in malathion-exposed larvae at a reduction of 22% and 29% for distance traveled and velocity, respectively. Gene regulation and enzymatic activity changes were measured for both 0.1 and 100 μg/L exposures across OP treatments. Increased CES activity was observed for the 0.1 μg/L treatments of diazinon and methyl-parathion as well as the 100 μg/L treatment of dichlorvos; meanwhile, decreased CES activity was observed for 100 μg/L treatments of diazinon and malathion. Relative enzymatic activity of AChE was inhibited as compared to the control for the 0.1 μg/L diazinon. No other treatment group exhibited a significant effect on biochemical AChE activity; however, AChE upregulation was observed in the 0.1 μg/L exposure for diazinon, dichlorvos, and malathion. Methyl-parathion was observed to downregulate c-Fos at 0.1 μg/L exposure. Malathion upregulated LINGO-1B at 100 μg/L, a gene associated with neuronal regeneration; meanwhile, downregulation of LINGO-1B was observed for 0.1 μg/L exposure of methyl-parathion. Additional downregulation was observed for GRIN-1B in the 100 μg/L diazinon, 100 μg/L dichlorvos, and 0.1 μg/L methyl-parathion treatments. Exposure of ZF embryos to independent concentrations of 100 μg/L concentrations of diazinon and malathion resulted in hypoactivity and decreased CES activity at 5 dfp. No changes in swimming behavior were observed for either the 0.1 μg/L or 100 μg/L dichlorvos or methyl-parathion treatments. Observations from this study indicate that AChE inhibition may not be the most sensitive biomarker of OP pesticide exposure in zebrafish. Rather, the enzyme CES demonstrated higher sensitivity as a biomarker of OP toxicity. Show less

To elucidate the genetic cause of a large 5 generation South Indian family with multiple individuals with predominantly an upper limb postural tremor and posturing in keeping with another form of tremor, namely, dystonic tremor. Whole-genome single nucleotide polymorphism (SNP) microarray analysis was undertaken to look for copy number variants in the affected individuals. Whole-genome SNP microarray studies identified a tandem duplicated genomic segment of chromosome 15q24 present in all affected family members. Whole-genome sequencing demonstrated that it comprised a ∼550-kb tandem duplication encompassing the entire The identification of a genomic duplication as the likely molecular cause of this condition, resulting in an additional Show less

Spinal cord injury (SCI) is a common demyelinating disorder of the central nervous system. The differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs), which induce myelination, plays a critical role in the functional recovery following SCI. In this study, the effect of low frequency pulsed electromagnetic field (PEMF) on the differentiation of OPCs and the potential underlying mechanisms were investigated. OPCs were randomly divided into the PEMF and non-PEMF (NPEMF) groups. Immunofluorescence and western blot assays were performed to assess the expression levels of OLs stage-specific markers after 3, 7, 14, and 21 days of PEMF or NPEMF exposure. qRT-PCR was used to further assess the expression levels of miR-219-5p, miR-338, miR-138, and miR-9, which are associated with OPCs differentiation, and the expression levels of genes associated with miR-219-5p. Finally, following PEMF or NPEMF exposure, qRT-PCR and western blot assays were performed to explore the relationship between miR-219-5p and Lingo1 and between miR-219-5p and PEMF in promoting OPCs differentiation. PEMF promoted the differentiation of OPCs. PEMF upregulated the expression level of miR-219-5p and downregulated the expression level of Lingo1 during the differentiation of OPCs. Under PEMF exposure, miR-219-5p targeted Lingo1 and reversed the inhibitory effect of miR-219-5p inhibitor on OPCs differentiation. In addition, PEMF synergized with miR-219-5p to promote OPCs differentiation. Our results, for the first time, indicated that PEMF promoted OPCs differentiation by regulating miR-219-5p activity in vitro. Show less

New insights on cellular and molecular aspects of both oligodendrocyte (OL) differentiation and myelin synthesis pathways are potential avenues for developing a cell-based therapy for demyelinating disorders comprising multiple sclerosis. MicroRNAs (miRNA) have broad implications in all aspects of cell biology including OL differentiation. MiR-184 has been identified as one of the most highly enriched miRNAs in oligodendrocyte progenitor cells (OPCs). However, the exact molecular mechanism of miR-184 in OL differentiation is yet to be elucidated. Based on immunochemistry assays, qRT-PCR, and western blotting findings, we hypothesized that overexpression of miR-184 in either neural progenitor cells (NPCs) or embryonic mouse cortex stimulated the differentiation of OL lineage efficiently through regulating crucial developmental genes. Luciferase assays demonstrated that miR-184 directly represses positive regulators of neural and astrocyte differentiation, i.e., SOX1 and BCL2L1, respectively, including the negative regulator of myelination, LINGO1. Moreover, blocking the function of miR-184 reduced the number of committed cells to an OL lineage. Our data highlighted that miR-184 could promote OL differentiation even in the absence of exogenous growth factors and propose a novel strategy to improve the efficacy of OL differentiation, with potential applications in cell therapy for neurodegenerative diseases. Show less

Leucine-rich repeat and immunoglobulin domain-containing protein 1 (LINGO-1) is a transmembrane protein that negatively regulates neural regeneration in the central nervous system. LINGO-1 expression is up-regulated after central nerve injury, and is accompanied by cell death. Both LINGO-1 and cell death in the injury microenvironment are thought to limit neural regeneration, but the relationship between LINGO-1 and cell death has not been characterized. To investigate whether LINGO-1 deletion improves the spinal cord microenvironment after spinal cord injury (SCI) and contributes to cell survival, we generated LINGO-1 knockout (KO) mice. These mice and wild-type control mice were subjected to spinal cord transection. Fourteen days after spinal cord transection, cell apoptosis, inflammation, glial scar, and growth of nerve fibers were evaluated by immunostaining. The results showed that LINGO-1 KO mice demonstrated a profound reduction in expression of caspase-3, transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL), ionized calcium binding adapter molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and chondroitin sulfate proteoglycans (CSPGs) compared to controls. In contrast, expression of neurofilament (NF) at the SCI site in LINGO-1 KO mice was markedly increased compared to that in wild-type mice. These results suggested that LINGO-1 plays a critical role in the injury microenvironment in processes such as cell death, inflammatory response, and glial scar formation. Importantly, LINGO-1 deletion and a positive microenvironment may exert synergistic effects to promote nerve fiber regeneration. Therefore, inhibition of LINGO-1 may be a therapeutic strategy to promote neural regeneration following SCI. Show less

Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis. We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18-58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov, number NCT01864148. Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment. Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose. Biogen. Show less

Suture and autologous nerve transplantation are the primary therapeutic measures for completely severed nerves. However, imbalances in the microenvironment and adhesion of surrounding tissues can affect the quality of nerve regeneration and repair. Previous studies have shown that human amniotic membrane can promote the healing of a variety of tissues. In this study, the right common peroneal nerve underwent a 5-mm transection in rats. Epineural nerve repair was performed using 10/0 non-absorbable surgical suture. The repair site was wrapped with a two-layer amniotic membrane with α-cyanoacrylate rapid medical adhesive after suture. Hindlimb motor function was assessed using footprint analysis. Conduction velocity of the common peroneal nerve was calculated by neural electrical stimulation. The retrograde axoplasmic transport of the common peroneal nerve was observed using fast blue BB salt retrograde fluorescent staining. Hematoxylin-eosin staining was used to detect the pathological changes of the common peroneal nerve sputum. The mRNA expression of axon regeneration-related neurotrophic factors and inhibitors was measured using real-time polymerase chain reaction. The results showed that the amniotic membrane significantly improved the function of the injured nerve; the toe spread function rapidly recovered, the nerve conduction velocity was restored, and the number of fast blue BB salt particles were increased in the spinal cord. The amniotic membrane also increased the recovery rate of the tibialis anterior muscle and improved the tissue structure of the muscle. Meanwhile, mRNA expression of nerve growth factor, growth associated protein-43, collapsin response mediator protein-2, and brain-derived neurotrophic factor recovered to near-normal levels, while Lingo-1 mRNA expression decreased significantly in spinal cord tissues. mRNA expression of glial-derived neurotrophic factor did not change significantly. Changes in mRNA levels were more significant in amniotic-membrane-wrapping-treated rats compared with model and nerve sutured rats. These results demonstrate that fresh amniotic membrane wrapping can promote the functional recovery of sutured common peroneal nerve via regulation of expression levels of neurotrophic factors and inhibitors associated with axonal regeneration. The study was approved by the Committee on Animal Research and Ethics at the Affiliate Hospital of Zunyi Medical University, China (approval No. 112) on December 1, 2017. Show less

Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neurological alterations associated with white matter injury and demyelination may underlie this link. However, whether disturbances in cerebral myelination contribute to the initiation of depression in epilepsy remains unclear. In the present study, we investigated the connection between demyelination disorders and the development of depression comorbidity in epilepsy. We first induced spontaneous recurrent epilepticus seizure (SRS) in young rats with pilocarpine. We then established depressive behaviors by recurrent forced swimming test and evaluate the depression state by sucrose preference test. The ratio of depression comorbidity in SRS rats was then calculated. Next, myelination in SRS-Depressed (SRS-D) rats was explored via PCR, western blotting, and immunohistochemistry for the key myelin promotion factor, Olig2 and inhibition factor, LINGO-1. Finally, in situ RNA hybridization of NCX3, one of the dominant Ca Show less

Migraine is the sixth most prevalent disease in the world and a substantial number of experiments have been conducted to analyze potential differences between the migraine brain and the healthy brain. Results from these investigations point to the possibility that development and aggravation of migraine may include grey matter plasticity. Nogo-type signaling is a potent plasticity regulating system in the CNS and consists of ligands, receptors, co-receptors and modulators with a dynamic age- and activity-related expression in cortical and subcortical regions. Here we investigated a potential link between migraine and five key Nogo-type signaling genes: Show less

Therapeutic antibodies have been successfully developed in neurology. However, their efficacy needs to overcome a main hurdle that is their limited access to the brain. Moreover, the multifactorial characteristics of many neurological diseases complicate the identification of a specific target. In this review, we present the neuroroprotective effect of some monoclonal antibodies and we summarize how they can interact with neurodegenerative and inflammatory processes. Monoclonal antibodies, such as natalizumab, that represent a major achievement in multiple sclerosis, have been approved in this indication and used in the routine practice. Also, they are still in a phase of development in degenerative diseases and mainly aim to counteract the aggregation of misfolded proteins such as amyloid beta or tau proteins. Another strategy in development of new monoclonal antibodies is to block physiological inhibitors of axonal growth and myelination such as Nogo-A or its co-transporter LINGO-1. Finally, the recent approbation by the FDA of monoclonal antibodies against CGRP for migraine treatment has been a major breakthrough that expanded the potential fields of application of antibodies in neurology. Thus, a lot of research efforts are now devoted to improve the galenic forms, the routes of administration and to extend these various approaches to other targets. Show less

To observe the changes of Nogo/NgR and Rho/ROCK signaling pathway-related gene and protein expression in rats with spinal cord injury (SCI) treated with electroacupuncture (EA) and to further investigate the possible mechanism of EA for treating SCI. Allen's method was used to create the SCI rat model. Sixty-four model rats were further subdivided into four subgroups, namely, the SCI model group (SCI), EA treatment group (EA), blocking agent Y27632 treatment group (Y27632) and EA+blocking agent Y27632 treatment group (EA+Y), according to the treatment received. The rats were subjected to EA and/or blocking agent Y27632 treatment. After 14 days, injured spinal cord tissue was extracted for analysis. The mRNA and protein expression levels were determined by real-time fluorescence quantitative PCR and Western blotting, respectively. Cell apoptosis changes in the spinal cord were evaluated by in situ hybridization. Hindlimb motor function in the rats was evaluated by Basso-Beattie-Bresnahan assessment methods. Except for RhoA protein expression, compared with the SCI model group, EA, blocking agent Y27632 and EA+blocking agent Y27632 treatment groups had significantly reduced mRNA and protein expression of Nogo-A, NgR, LINGO-1, RhoA and ROCK II in spinal cord tissues, increased mRNA and protein expression of MLCP, decreased p-MYPT1 protein expression and p-MYPT1/MYPT1 ratio, and caspase3 expression, and improved lower limb movement function after treatment for 14 days (P<0.01 or <0.05). The combination of EA and the blocking agent Y27632 was superior to EA or blocking agent Y27632 treatment alone (P < 0.01 or <0.05). EA may have an obvious inhibitory effect on the Nogo/NgR and Rho/ROCK signaling pathway after SCI, thereby reducing the inhibition of axonal growth, which may be a key mechanism of EA treatment for SCI. Show less

The use of autologous bio-engineered dermo-epidermal skin substitutes (DESS) yields a pivotal opportunity to cover large skin defects in human patients. These skin grafts consist of both epidermal and dermal compartments necessary for robust and permanent functional wound closure. In this study, we investigated the impact of mesenchymal cells derived from different body site origins on the expression pattern of diverse markers within DESS. Human keratinocytes were obtained from interfollicular epidermis, and mesenchymal cells were isolated from foreskin, palmar skin, fat tissue, and tonsils. After expansion, epidermal cells were seeded on collagen I hydrogels containing stromal cells. These human DESS were transplanted on the back of immune-incompetent rats. After 3 weeks, transplants were excised and analyzed using immunohistology techniques. The macroscopic appearance of skin grafts containing tonsil, fat tissue, or palmar derived mesenchymal cells, was similar to substitutes with foreskin derived dermal fibroblasts. All skin grafts had a strong membrane-localized expression of Lingo-1 in the epidermis. Additionally, we observed an intense expression of transglutaminase 5 in upper epidermal cell layers of the skin grafts confirming a proper keratinocyte differentiation. Tropoelastin was localized throughout the dermal compartments and tightly in contact with the dermo-epidermal junction suggesting an advanced maturation of all skin grafts. Our data implicate that stromal cells derived from tonsil, fat tissue, and palmar skin can assume fibroblast functions supporting keratinocyte proliferation and differentiation. These findings indicate that distinct types of mesenchymal cells can be clinically used for skin engineering purposes. Show less

In multiple sclerosis, demyelination occurs as a consequence of chronic autoimmunity in the central nervous system causing progressive neurological impairment in patients. After a demyelinating event, new myelin sheaths are formed by adult oligodendroglial progenitor cells; a process called remyelination. However, remyelination often fails in multiple sclerosis due to insufficient recruitment and differentiation of oligodendroglial precursor cells. A pivotal role for the two-pore-domain potassium (K Show less

Multiple evidence has indicated that myelin injury is common in Alzheimer's disease (AD). However, whether myelin injury is an early event in AD and the relationship between it and cognitive function is still elusive. Spatial memory of 5XFAD mice was determined by Morris water maze at 1 and 3 months old. Meanwhile, the deposition of Aβ, the expression of myelin basic protein (MBP), LINGO-1, NgR, and myelin ultrastructure in many memory-associated brain regions were detected in one-month-old and three-month-old mice (before and after LINGO-1 antibody administration) using immunostaining, Western blot (WB), and transmission electron microscopy (TEM), respectively. No abnormal Aβ deposition was found in one-month-old 5XFAD mice. However, spatial memory deficits were proved in accordance with an obvious demyelination in memory-associated brain regions in one-month-old mice and both deteriorated with age. Administration of LINGO-1 antibody could obviously restore the myelin impairments in CA1 and DG region and partially ameliorate spatial memory deficits. Our results demonstrated that myelin injury was an early event in 5XFAD mice even prior to emergence of deposition of Aβ. Intervention with the LINGO-1 antibody could attenuate impaired spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments. Show less

Glioblastoma is the most prevalent malignant glioma in WHO grade IV and its median overall survival is 12-15 months. This study identifies the primary glioblastoma. prognostic genes. Gene expression data in primary glioblastomas with short-term (36 months, N=23) overall survival were downloaded from Gene Expression Omnibus (GSE53733). Limma determined the differentially expressed genes (DEGs) between different groups (|log2 fold change| ≥0.5 and p-value DEG's degree, betweenness, sub-graph and closeness centralities. Long- term/short-term survival-related DEGs were defined as those with increased/decreased expression values and survival time. The following DEGs were identified; 161 between intermediate and short-term glioblastomas, 465 between long-term and short-term and 624 between long-term and intermediate tumors. The common FLRT1 and LINGO1 up-regulated DEGs and common down-regulated C7orf31 were identified in these three DEG sets. PPI networks were established, and VEGFA was the key DEG in each PPI network. The short-term survival-related DEGs were enriched in 3 cancer-related pathways. Moreover, FLRT1 and LINGO1 were long-term survival-related DEGs and C7orf31 and VEGFA were short-term survival DEGs. LINGO1, C7orf31, and VEGFA were confirmed using a further dataset, and we therefore conclude that LINGO1 might be a positive primary glioblastoma prognostic gene and C7orf31 and VEGFA might be negative prognosticators. Show less

Our previous studies showed interaction of Nogo at the midline with its receptor (NgR) on optic axons plays a role in axon divergence at the mouse optic chiasm. Since NgR lacks a cytoplasmic domain, it needs transmembrane receptor partners for signal transduction. In this study, we examined whether the co-receptors of NgR, low-affinity neurotrophic receptor (p75 Show less

Ewing sarcoma (ES), an aggressive bone and soft-tissue tumor, is treated with chemotherapy, radiotherapy, and surgery. Intra-operative distinction between healthy and tumorous tissue is of paramount importance but challenging, especially after chemotherapy and at complex anatomical locations. Near infrared (NIR) fluorescence-guided surgery (FGS) is able to facilitate the determination of tumor boundaries intra-operatively, improving complete resection and therefore survival. This review evaluates potential ES-specific proteins from the literature as targets for NIR FGS. Show less

Postnatal administration of phencyclidine (PCP) in rodents causes major brain dysfunction leading to severe disturbances in behavior lasting into adulthood. This model is routinely employed to model psychiatric disorders such as schizophrenia, as it reflects schizophrenia-related brain disturbances including increased apoptosis, and disruptions to myelin and plasticity processes. Leucine-rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1) is a potent negative regulator of both axonal myelination and neurite extension. The Nogo receptor (NgR)/tumor necrosis factor (TNF) receptor orphan Y (TROY) and/or p75 neurotrophin receptor (p75) complex, with no lysine (K) (WNK1) and myelin transcription factor 1 (Myt1) are co-receptors or cofactors in Lingo-1 signaling pathways in the brain. We have examined the developmental trajectory of these proteins in a neurodevelopmental model of schizophrenia using PCP to determine if Lingo-1 pathways are altered in the prefrontal cortex throughout different stages of life. Sprague-Dawley rats were injected with PCP (10 mg/kg) or saline on postnatal days (PN)7, 9, and 11 and killed at PN12, 5 or 14 weeks for measurement of Lingo-1 signaling proteins in the prefrontal cortex. Myt1 was decreased by PCP at PN12 ( Show less

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), have been on the forefront of drug discovery for most of the myelin inhibitory molecules implicated in axonal regenerative process. Nogo-A along with its putative receptor NgR and co-receptor LINGO-1 has paved the way for the production of pharmaceutical agents such as monoclonal antibodies, which are already put into handful of clinical trials. On the other side, little progress has been made towards clarifying the role of neurotrophin receptor p75 (p75NTR) and TROY in disease progression, other key players of the Nogo receptor complex. Previous work of our lab has shown that their exact location and type of expression is harmonized in a phase-dependent manner. Here, in this review, we outline their façade in normal and diseased central nervous system (CNS) and suggest a role for p75NTR in chronic axonal regeneration whereas TROY in acute inflammation of EAE intercourse. Show less

Multifocal visual evoked potential (MF-VEP) assesses a wider visual field than full-field VEP (FF-VEP) and potentially offers a more precise analysis of optic nerve injury and repair following optic neuritis. MF-VEP may offer advantages over FF-VEP as an endpoint in clinical trials of remyelinating therapies. MF-VEP testing was used to study changes in visual pathways in 48% of RENEW [phase II, opicinumab (anti-LINGO-1; BIIB033) vs. placebo after first acute unilateral optic neuritis] participants. This exploratory MF-VEP RENEW substudy compared mean outcomes at weeks 24 and 32 among participants in the intent-to-treat (ITT; n = 39; 72% female; mean age: 32.3 years) and per-protocol (PP; n = 31; 71% female; mean age: 32.2 years) populations in affected and fellow eye latency from fellow eye baseline latency and affected and fellow eye amplitude from their own baselines. Treatment differences were evaluated using analysis of covariance (week 24) and a mixed-effect model of repeated measures (week 32). Last observation carried forward was used to impute missing data at week 24. A trend for improvement in affected eye MF-VEP latency with opicinumab versus placebo was seen in the ITT and PP populations at weeks 24 and 32. Both treatment groups in the ITT population experienced partial recovery of amplitude in the affected eye at week 32. Notably, the mean change in fellow eye amplitude at weeks 24 and 32 was - 17.57 and - 31.41 nanovolts (nV) in placebo but only - 0.59 and 1.93 nV in the opicinumab group [differences at weeks 24 and 32: 16.98 nV (p = 0.050) and 33.33 nV (p < 0.01), respectively]. Results from this substudy showed advantages of MF-VEP over FF-VEP in multicenter studies of central nervous system reparative therapies and provide novel evidence that fellow eye visual pathway amplitude loss occurs after optic neuritis but can potentially be prevented by opicinumab treatment. ClinicalTrials.gov identifier NCT01721161. Show less

To evaluate whether the anti-LINGO-1 antibody has immunomodulatory effects. Human peripheral blood mononuclear cells (hPBMCs), rat splenocytes, and rat CD4 LINGO-1 is not expressed in hPBMCs, rat splenocytes, or rat CD4 These data support the hypothesis that LINGO-1 blockade does not affect immune function. This study provides Class II evidence that in patients with MS, opicinumab does not have immunomodulatory effects detected by changes in immune gene transcript expression. Show less

Seizure-induced brain damage is age-dependent, as evidenced by the different alterations of neural physiopathology in developing and mature brains. However, little is known about the age-dependent characteristics of myelinated fiber injury induced by seizures. Considering the critical functions of oligodendrocyte progenitor cells (OPCs) in myelination and Lingo-1 signaling in regulating OPCs' differentiation, the present study aimed to explore the effects of Lingo-1 on myelin and axon in immature and adult rats after status convulsion (SC) induced by lithium-pilocarpine, and the differences between immature and adult brains. Dynamic variations in electrophysiological activity and spontaneous recurrent seizures were recorded by electroencephalogram monitoring after SC. The impaired microstructures of myelin sheaths and decrease in myelin basic protein caused by SC were observed through transmission electron microscopy and western blot analysis respectively, which became more severe in adult rats, but improved gradually in immature rats. Aberrant axon sprouting occurred in adult rats, which was more prominent than in immature rats, as shown by a Timm stain. This damage was improved or negatively affected after down or upregulating Lingo-1 expression. These results demonstrated that in both immature and adult brains, Lingo-1 signaling plays important roles in seizure-induced damage to myelin sheaths and axon growth. The plasticity of the developing brain may provide a potential window of opportunity to prevent the brain from damage. Show less

An appropriate strength of Nogo-like signaling is important to maintain synaptic homeostasis in the CNS. Disturbances have been associated with schizophrenia, MS and other diseases. Blocking Nogo-like signaling may improve recovery after spinal cord injury, stroke and traumatic brain injury. To understand the interacting roles of an increasing number of ligands, receptors and modulators engaged in Nogo-like signaling, the transcriptional activity of these genes in the same brain areas from birth to old age in the normal brain is needed. Thus, we have quantitatively mapped the innate expression of 11 important genes engaged in Nogo-like signaling. Using Show less

To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability. A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software. All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein. LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans. Show less

After injury to the mature central nervous system (CNS), myelin-derived inhibitory ligands bind to the Nogo-66 tripartite receptor complex expressed on axonal growth cones, comprised of LINGO-1 and p75 Show less

Leucine rich repeat proteins have gained considerable interest as therapeutic targets due to their expression and biological activity within the central nervous system. LINGO-1 has received particular attention since it inhibits axonal regeneration after spinal cord injury in a RhoA dependent manner while inhibiting leucine rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1) disinhibits neuron outgrowth. Furthermore, LINGO-1 suppresses oligodendrocyte precursor cell maturation and myelin production. Inhibiting the action of LINGO-1 encourages remyelination both Show less

Differentiation and maturation of oligodendrocyte progenitor cells (OPCs) involve the assembly and disassembly of actin microfilaments. However, how actin dynamics are regulated during this process remains poorly understood. Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) is a negative regulator of OPC differentiation. We discovered that anti-LINGO-1 antibody-promoted OPC differentiation was accompanied by upregulation of cytoplasmic gelsolin (cGSN), an abundant actin-severing protein involved in the depolymerization of actin filaments. Treating rat OPCs with cGSN siRNA reduced OPC differentiation, whereas overexpression of cGSN promoted OPC differentiation Show less

Essential tremor (ET) is one of the most common movement disorders. Its clinical manifestations not only include typical kinetic and/or postural tremors, but also other non-motor symptoms such as cognitive dysfunction, sleep disturbance, and dysosmia. The exact etiology and pathogenesis of ET is still unknown. Approximately 60% of ET patients have a family history, and genetic factor plays an important role in the onset of the disease. Researchers have so far identified 3 genetic loci (ETM 1-3) through family studies, and proposed additional causative genes such as FUS, HTRA2, TENM4, NOS3 and susceptibility genes such as LINGO, SLC1A2, and GABA. This review focuses on the progress made in genetic research on ET. Show less

We previously mapped loci for the genome-wide association studies (GWAS) and genome-wide gene-by-alcohol dependence interaction (GW-GxAD) analyses of risky sexual behaviors (RSB). This study extends those findings by analyzing the ancestry- and sex-specific AD-stratified effects on RSB. We examined the concordance of findings for the AD-stratified GWAS and the GW-GxAD analysis of RSB, with concordance defined as genome-wide significance in one analysis and at least nominal significance in the second analysis. A total of 2,173 African-American (AA) and 1,751 European-American (EA) subjects were investigated. Information regarding RSB (lifetime experiences of unprotected sex and multiple sexual partners) and DSM-IV diagnosis of lifetime AD were derived from the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). In our ancestry- and sex-specific analyses, we identified four independent genome-wide significant (GWS) loci (p < 5*10 Show less