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Chronic stress can induce cognitive impairment, and synapse number was significantly decreased in the hippocampus of rats suffering from chronic stress. Lingo-1 is a potent negative regulator of axonal outgrowth and synaptic plasticity. In the current study, the effects of anti-Lingo-1 antibody on the spatial learning and memory abilities and hippocampal synapses of stressed rats were investigated. After 4 weeks of stress exposure, the model group was randomly divided into a chronic stress group and an anti-Lingo-1 group. Then, the anti-Lingo-1 group rats were treated with anti-Lingo-1 antibody (8 mg/kg) for 3 weeks. The effects of anti-Lingo-1 antibody on the spatial learning and memory abilities were investigated with the Morris water maze test. Immunohistological staining and an unbiased stereological method were used to estimate the total number of dendritic spine synapses in the hippocampus. At the behavioral level, after 3 weeks of treatment, the anti-Lingo-1 group rats displayed significantly more platform location crossings in the Morris water maze test than the chronic stress group rats. Anti-Lingo-1 significantly prevented the declines in dendritic spine synapses and postsynaptic density protein-95 (PSD-95) expression in the dentate gyrus and the CA1 and CA3 regions of the hippocampus. The present results indicated that anti-Lingo-1 antibody may be a safe and effective drug for alleviating memory impairment in rats after chronic stress and protecting synapses in the hippocampus of stressed rats. Show less

LINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen-glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke. Show less

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG) Show less

There are many reports suggesting an important role of genetic factors in the etiopathogenesis of essential tremor (ET), encouraging continuing the research for possible genetic markers. Linkage studies in families with ET have identified 4 genes/loci for familial ET, although the responsible gene(s) have not been identified. Genome-wide association studies (GWAS) described several variants in Show less

Manipulation of neural stem and progenitor cells (NSPCs) is critical for the successful treatment of spinal cord injury (SCI) by NSPC transplantation, since their differentiation into neurons and oligodendrocytes can be inhibited by factors present in inflamed myelin. In this study, we examined the effects of LINGO-1 on spinal cord-derived NSPC (sp-NSPC) differentiation, the underlying mechanisms of action, and the functional recovery of mice after transplantation of manipulated cells. sp-NSPCs were harvested from female adult C57/BL6 mice after SCI induced with an NYU impactor. These cells were infected with lentiviral vectors containing LINGO-1 shRNA sequence or a scrambled control and transplanted into SCI mice. Tuj-1- and GFAP-positive cells were assessed by immunofluorescence staining. Wnt5a, p-JNK, JNK, and β-catenin expression was determined by Western blot and RT-qPCR. miRNAs were sequenced to detect changes in miRNA expression. Motor function was evaluated 0-35 days post-surgery by means of the Basso Mouse Scale (BMS) and by the rotarod performance test. We discovered that LINGO-1 shRNA increased neuronal differentiation of sp-NSPCs while decreasing astrocyte differentiation. These effects were accompanied by elevated Wnt5a protein expression, but unexpectedly, no changes in Wnt5a mRNA levels. miRNA-sequence analysis demonstrated that miR-15b-3p was a downstream mediator of LINGO-1 which suppressed Wnt5a expression. Transplantation of LINGO-1 shRNA-treated sp-NSPCs into SCI mice promoted neural differentiation, wound compaction, and motor function recovery. LINGO-1 shRNA promotes neural differentiation of sp-NSPCs and Wnt5a expression, probably by downregulating miR-15b-3p. Transplantation of LINGO-1 shRNA-treated NSPCs promotes recovery of motor function after SCI, highlighting its potential as a target for SCI treatment. Show less

The purpose of this study was to determine the dynamic changes of the Nogo-66 receptor 1 (NgR1) pathway during epileptogenesis and the potential beneficial of leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1 (Lingo-1) inhibition on epilepsy rats. The hippocampal changes of the NgR1 pathway during epileptogenesis were determined by western blot analysis of multiple proteins, including neurite outgrowth inhibitor protein A (NogoA), myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), Lingo-1, ras homolog family member A (RhoA) and phosphorylated RhoA (p-RhoA). Lentivirus-mediated short hairpin RNA (shRNA) was used to knockdown the hippocampal expression of Lingo-1. Novel object recognition (NOR) test and Morris Water Maze (MWM) test were employed to determine the cognitive functions of rats. Hematoxylin and eosin (H&E) staining, protein expressions of RhoA, p-RhoA, and myelin basic protein (MBP), as well as convulsion susceptibility test were additionally performed. Our results showed that the NgR1 pathway was activated during epileptogenesis, characterized by up-regulation of NogoA, MAG, OMgp, and Lingo-1, which was especially significant at the chronic phase of epilepsy. The cognitive function, convulsion susceptibility and hippocampal neuronal survival of rats were impaired at the chronic phase of epileptogenesis but all improved by Lingo-1 inhibition; besides, the hippocampal protein expressions of p-RhoA and MBP were significantly decreased at the chronic phase of SC rats but increased after Lingo-1 inhibition. Our results demonstrated that Lingo-1 shRNA can improve epilepsy-induced cognitive impairment, which may be related with the pro-myelination and neuroprotection effects of Lingo-1 inhibition. Show less

At present, the effect of ganglioside combined with Jiaji electroacupuncture (Jiaji EA) on SCI still remains unclear. This study explores the effect of ganglioside combined with electroacupuncture on Nogo/NgR signal pathway in spinal cord tissue of spinal cord injury (SCI) rats. Basso Beattie Bresnahan (BBB) score was used to evaluate spinal cord function after modeling and 14 days post ganglioside and electroacupuncture treatment. RT-qPCR and western blot were performed to evaluate the expression levels of targets in spinal cord tissue. After 14 days of treatment, the BBB scores of Jiaji EA group, ganglioside group and combination group were all improved. The expression levels of IL-1β, IL-6 and TNF-α in Jiaji EA group, ganglioside group and combination group were significantly lower than those in model group. Both of mRNA and protein expression levels of Nogo-A, NgR and LINGO-1 in the model group were significantly higher than those in the Jiaji EA group, ganglioside group and combination group. Ganglioside combined with Jiaji EA has a stronger effect on promoting the recovery of nerve function. Its mechanism of action may be related to its inhibition of the expression of proinflammatory cytokines such as IL-1β, IL-6 and TNF-α and Nogo-NgR signal pathway to promote neuronal growth. Our results will provide fundamental information for further SCI studies. Show less

Alzheimer's disease (AD) is implicated in the imbalance of several proteins, including Amyloid-β (Aβ), amyloid precursor protein (APP), and BACE1. APP overexpression interferes with neurite outgrowth, while BACE1 plays a role in Aβ generation. Medicinal herbs with effects on neurite outgrowth stimulation and BACE1 inhibition may benefit AD. This study aimed to investigate the neurite outgrowth stimulatory effect, along with BACE1 inhibition of Show less

Alzheimer's disease (AD) is a pervasive age-related and highly heritable neurodegenerative disorder but has no effective therapy. The complex cellular microenvironment in the AD brain impedes our understanding of pathogenesis. Thus, a comprehensive investigation of cell type-specific responses in AD is crucial to provide precise molecular and cellular targets for therapeutic development. Here, we integrated analyzed 4,441 differentially expressed genes (DEGs) that were identified from 263,370 single-cells in cortex samples by single-nucleus RNA sequencing (snRNA-seq) between 42 AD-pathology subjects and 39 normal controls within 3 studies. DEGs were analyzed in microglia, astrocytes, oligodendrocytes, excitatory neurons, inhibitory neurons, and endothelial cells, respectively. In each cell type, we identified both common DEGs which were observed in all 3 studies, and overlapping DEGs which have been seen in at least 2 studies. Firstly, we showed the common DEGs expression and explained the biological functions by comparing with existing literature or multil-omics signaling pathways knowledgebase. We then determined the significant modules and hub genes, and explored the biological processes using the overlapping DEGs. Finally, we identified the common and distinct dysregulated pathways using overall DEGs and overlapping DEGs in a cell type-specific manner. Up-regulated LINGO1 has been seen in both oligodendrocytes and excitatory neurons across 3 studies. Interestingly, genes enriched in the mitochondrial module were up-regulated across all cell types, which indicates mitochondrial dysfunction in the AD brain. The estrogen signaling pathway seems to be the most common pathway that is disrupted in AD. Together, these analyses provide detailed information of cell type-specific and overall transcriptional changes and pathways underlying the human AD-pathology. These findings may provide important insights for drug development to tackle this disease. Show less

Leucine rich repeat and immunoglobulin-like domain-containing protein 1 (Lingo-1) has gained considerable interest as a potential therapy for demyelinating diseases since it inhibits axonal regeneration and myelin production. However, the results of clinical trials targeted at Lingo-1 have been unsatisfactory. Amphoterin-induced gene and open reading frame-3 (AMIGO3), which is an analog of Lingo-1, might be an alternative therapeutic target for brain damage. In the present study, we investigated the effects of AMIGO3 on neural circuits in immature mice after status convulsion (SC) induced by kainic acid. The expression of both AMIGO3 and Lingo-1 was significantly increased after SC, with levels maintained to 20 days after SC. Following SC, transmission electron microscopy revealed the impaired microstructure of myelin sheaths and Western blot analysis showed a decrease in myelin basic protein expression, and this damage was alleviated by downregulation of AMIGO3 expression. The ROCK/RhoA signaling pathway was inhibited at 20 days after SC by downregulating AMIGO3 expression. These results indicate that AMIGO3 plays important roles in seizure-induced damage of myelin sheaths as well as axon growth and synaptic plasticity via the ROCK/RhoA signaling pathway. Show less

Central nervous system demyelination is the main feature of multiple sclerosis (MS). The most important unmet need in MS is use of treatments that delay the progression of the disease. Leucine-rich repeat and Immunoglobulin-like domain containing NOGO receptor-interacting protein 1(LINGO-1) have been known as inhibitors of oligodendrocyte differentiation and myelination. We investigated LINGO-1 antibody effects on remyelination and neurobehavioral deficit using cuprizone-induced demyelination. Animals were randomly divided into three groups (n = 10): (1) Control group; received the regular diet, (2) CPZ group; normal saline was injected intraperitoneally, and (3) Treatment group; LINGO-1 antibody (10 mg/kg) was injected IP once every six days for 3 weeks. We assessed the level of myelin basic protein (MBP), neurofilament heavy chain (NF200), and Brain-derived neuroprotective factor (BDNF) in the corpus callosum (CC) by immunostaining against MBP, NF200, and BDNF. We found decreased levels of MBP, NF200, and BDNF in demyelinated CC, and anti-LINGO-1 treatment improved demyelinated structures. Furthermore, motor impairment was measured by Open-field (OFT) and Balance beam tests. In the treatment group, motor impairment was significantly improved. These results provide evidence that LINGO-1 antibody can improve remyelination and neurobehavioral deficit. Show less

Shift work is widespread due to 24-h work in many occupations. Understanding differences in individual shift work tolerance (SWT) can help develop coping strategies for shift workers. This in-depth qualitative review elucidates the architecture of SWT, providing an overview of the research advances in the last decade (2011-2021). We searched Google Scholar, PubMed and Medline for different word combinations concerning SWT. Genome-wide association studies (GWAS) for the potential genetic basis of SWT were additionally searched in GWAS Central and GWAS Catalogue. Eleven new studies were published since 2011, with the proportion of longitudinal studies on SWT having more than doubled in the past decade. They consolidate prior findings (e.g. hardiness most consistently associated with SWT) and discovered additional aspects of SWT like resistance to change and job stress. The 15 large-scale GWAS identified, most of which using UK Biobank (UKB) and 23andMe data, involved mapped genes showing overlap especially within analysis of the same phenotype (e.g. PER2/3 for morningness, PAX8 for sleep duration and LINGO1 for neuroticism). Individual GWAS for additional traits such as resilience have also been published though assessments of gene overlap are not yet possible. Progress regarding longitudinal studies on SWT has been made though a more consistent definition of SWT remains crucial for future research. Non-genetic studies on SWT suggest several important traits and factors; many of which have now also been explored using GWAS. Such evidence could serve as basis for individualized risk prediction and disease prevention approaches for night-shift workers. Show less

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aβ) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future. Show less

Alzheimer's disease (AD) is a devastating neurodegenerative condition provoking the loss of cognitive and memory performances. Despite huge efforts to develop effective AD therapies, there is still no cure for this neurological condition. Here, we review the main biological properties of Phycocyanobilin (PCB), accounting for its potential uses against AD. PCB, given individually or released in vivo from C-Phycocyanin (C-PC), acts as a bioactive-molecule-mediating antioxidant, is anti-inflammatory and has immunomodulatory activities. PCB/C-PC are able to scavenge reactive oxygen and nitrogen species, to counteract lipid peroxidation and to inhibit enzymes such as NADPH oxidase and COX-2. In animal models of multiple sclerosis and ischemic stroke, these compounds induce remyelination as demonstrated by electron microscopy and the expression of genes such as Show less

How the evolution of complex behavioral traits is associated with the emergence of novel brain pathways is largely unknown. Songbirds, like humans, learn vocalizations via tutor imitation and possess a specialized brain circuitry to support this behavior. In a comprehensive in situ hybridization effort, we show that the zebra finch vocal robust nucleus of the arcopallium (RA) shares numerous markers (e.g. SNCA, PVALB) with the adjacent dorsal intermediate arcopallium (AId), an avian analog of mammalian deep cortical layers with involvement in motor function. We also identify markers truly unique to RA and thus likely linked to modulation of vocal motor function (e.g. KCNC1, GABRE), including a subset of the known shared markers between RA and human laryngeal motor cortex (e.g. SLIT1, RTN4R, LINGO1, PLXNC1). The data provide novel insights into molecular features unique to vocal learning circuits, and lend support for the motor theory for vocal learning origin. Show less

LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2 clinical trial as a potential treatment for individuals with relapsing forms of multiple sclerosis (AFFINITY: clinical trial.gov number NCT03222973). Li81 has the unusual feature that it contains two LINGO-1 binding sites: a classical site utilizing its complementarity-determining regions and a cryptic secondary site involving Li81 light chain framework residues that recruits a second LINGO-1 molecule only after engagement of the primary binding site. Concurrent binding at both sites leads to formation of a 2:2 complex of LINGO-1 with the Li81 antigen-binding fragment, and higher order complexes with intact Li81 antibody. To elucidate the role of the secondary binding site, we designed a series of Li81 variant constructs that eliminate it while retaining the classic site contacts. These Li81 mutants retained the high affinity binding to LINGO-1, but lost the antibody-induced oligodendrocyte progenitor cell (OPC) differentiation activity and myelination activity in OPC- dorsal root ganglion neuron cocultures seen with Li81. The mutations also attenuate antibody-induced internalization of LINGO-1 on cultured cortical neurons, OPCs, and cells over-expressing LINGO-1. Together these studies reveal that engagement at both LINGO-1 binding sites of Li81 is critical for robust functional activity of the antibody. Show less

Chronic cerebral hypoperfusion is a common cause of cerebral small vascular disease (CSVD). White matter (WM) lesions are the typical pathological manifestation of CSVD and contribute to cognitive decline. Epimedium flavonoids (EF) are the main component in Epimedium brevicornu Maxim., which is commonly used in traditional Chinese medicine. The purpose of this study was to investigate the effects of EF on cognitive impairment and the underlying mechanisms in a CSVD rat model induced with chronic cerebral hypoperfusion. The model was established by permanent bilateral common carotid artery occlusion (2VO) in rats. EF (50, 100, and 200 mg/kg) was intragastrically administered once a day for 12 weeks starting 2 weeks after 2VO surgery. The learning and memory capacity of the rats were measured using the Morris water maze and step-through tests. WM lesions were observed by MRI-diffusion tensor imaging, transmission electron microscopy, and LFB staining. Oligodendrocytes were detected by immunohistochemistry. Western blotting assay was used to determine the level of protein expression. The results showed that EF significantly improved learning and memory impairment, alleviated WM nerve fiber injuries and demyelination, and increased the number of mature oligodendrocytes in the corpus callosum, subcortical WM, and periventricular WM in 2VO rats. Mechanistically, EF reduced the expression of Lingo-1 and ROCK2 and increased the levels of phosphorylated (p-) Fyn, brain-derived neurotrophic factor (BDNF), TrkB, neuregulin-1 (NRG-1), p-ErbB4, PI3K p85 and p110α, p-Akt, and p-CREB in the corpus callosum of 2VO rats. These results suggest that EF may improve cognitive impairment and WM lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/TrkB, NRG-1/ErbB4, and the downstream PI3K/Akt/CREB pathways in WM. Thus, EF can be used as a potential neuroprotective agent in CSVD therapy. Show less

Chronic exposure to stressful conditions may affect spatial learning and memory abilities and the brain structure, and disruptions in oligodendrocyte function may cause cognitive dysfunction. Leucine-rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1) is a potent negative regulator of oligodendrocytes and axon myelination. However, the questions we sought to answer in this study are whether hippocampal oligodendrocytes are involved in the pathological process of spatial learning and memory impairments induced by chronic stress (CS) and whether antibodies targeting LINGO-1 improve stress-induced spatial learning and memory impairments by protecting the hippocampal oligodendrocytes in stressed rats. After 4 weeks of CS, rats were randomly divided into either the CS standard group or anti-LINGO-1 group. The anti-LINGO-1 group was treated with an anti-LINGO-1 antibody (8 mg/kg) for 3 weeks; all rats were assessed in the Morris water maze. Immunohistochemical staining and modern stereological methods were used to precisely quantify the total number of 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive (CNPase Show less

Insults to the axons in the optic nerve head are the primary cause of loss of retinal ganglion cells (RGCs) in traumatic, ischemic nerve injury or degenerative ocular diseases. The central nervous system-specific leucine-rich repeat protein, LINGO-1, negatively regulates axon regeneration and neuronal survival after injury. However, the upstream molecular mechanisms that regulate LINGO-1 signaling and contribute to LINGO-1-mediated death of RGCs are unclear. The expression of SP1 was profiled in optic nerve crush (ONC)-injured RGCs. LINGO-1 level was examined after SP1 overexpression by qRT-PCR. Luciferase assay was used to examine the binding of SP1 to the promoter regions of LINGO-1. Primary RGCs from rat retina were isolated by immunopanning and RGCs apoptosis were determined by Tunnel. SP1 and LINGO-1 expression was investigated using immunohistochemistry and Western bolting. Neuroprotection was assessed by RGC counts, RNFL thickness, and VEP tests after inhibition of SP1 shRNA. We demonstrate that SP1 was upregulated in ONC-injured RGCs. SP1 was bound to the LINGO-1 promoter, which led to increased expression of LINGO-1. Treatment with recombinant Nogo-66 or LINGO-1 promoted apoptosis of RGCs cultured under serum-deprivation conditions, while silencing of SP1 promoted the survival of RGCs. SP1 and LINGO-1 colocalized and were upregulated in ONC-injured retinas. Silencing of SP1 in vivo reduced LINGO-1 expression and protected the structure of RGCs from ONC-induced injury, but there was no sign of recovery in VEP. Our findings imply that SP1 regulates LINGO-1 expression in RGCs in the injured retina and provide insight into mechanisms underlying LINGO-1-mediated RGC death in optic nerve injury. Show less

Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis; however, no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP. Leucine-rich repeat and immunoglobulin-like domain-containing protein-1 (LINGO-1) activates the Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathway, which negatively regulates oligodendrocyte myelination, axonal growth, and neuronal survival, causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases. However, whether LINGO-1 is involved in DEACMP remains unclear. A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes, followed by 3000 ppm carbon monoxide gas for an additional 20 minutes. The results showed that compared with control rats, DEACMP rats showed significantly increased water maze latency and increased protein and mRNA expression levels of LINGO-1, RhoA, and ROCK2 in the brain. Compared with normal rats, significant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats. From days 1 to 21 after DEACMP, the intraperitoneal injection of retinoic acid (10 mg/kg), which can inhibit LINGO-1 expression, was able to improve the above changes observed in the DEACMP model. Therefore, the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning, activating the RhoA/ROCK2 signaling pathway, which may be an important pathophysiological mechanism underlying DEACMP. This study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital (approval No. 201612684) on December 26, 2016. Show less

Neuroplasticity and connectivity in the central nervous system (CNS) are easily damaged after hypoxia. Long-term exposure to an anoxic environment can lead to neuropsychiatric symptoms and increases the likelihood of depression. Demyelination is an important lesion of CNS injury that may occur in depression. Previous studies have found that the RhoA/ROCK pathway is upregulated in neuropsychiatric disorders such as multiple sclerosis, stroke, and neurodegenerative diseases. Therefore, the chief aim of this study is to explore the regulatory role of the RhoA/ROCK pathway in the development of depression after hypoxia by behavioral tests, Western blotting, immunostaining as well as electron microscopy. Results showed that HIF-1α, S100β, RhoA/ROCK, and immobility time in FST were increased, sucrose water preference ratio in SPT was decreased, and the aberrant activity of neurocyte and demyelination occurred after hypoxia. After the administration of Y-27632 and fluoxetine in hypoxia, these alterations were improved. Lingo1, a negative regulatory factor, was also overexpressed after hypoxia and its expression was decreased when the pathway blocked. However, fluoxetine had no effect on the expression of Lingo1. Then, we demonstrated that demyelination was associated with failures of oligodendrocyte precursor cell proliferation and differentiation and increased apoptosis of oligodendrocytes. Collectively, our data indicate that the RhoA/ROCK pathway plays a vital role in the initial depression during hypoxia. Blocking this pathway in the early stage of hypoxia can enhance the effectiveness of antidepressants, rescue myelin damage, and reduce the expression of the negative regulatory protein of myelination. The findings provide new insight into the prophylaxis and treatment of depression. Show less

In the current review, we thoroughly reviewed 74 identified articles regarding genes and genetic loci that confer susceptibility to ET. Over 50 genes/genetic loci have been examined for possible association with ET, but consistent results failed to be reported raising the need for collaborative multiethnic studies. Essential tremor (ET) is a common movement disorder, which is mainly characterized by bilateral tremor (postural and/or kinetic) in the upper limbs, with other parts of the body possibly involved. While the pathophysiology of ET is still unclear, there is accumulating evidence indicating that genetic variability may be heavily involved in ET pathogenesis. This review focuses on the role of genetic risk factors in ET susceptibility. The PubMed database was searched for articles written in English, for studies with humans with ET, controls without ET, and genetic variants. The terms "essential tremor" and "polymorphism" (as free words) were used during search. We also performed meta-analyses for the most examined genetic variants. Seventy four articles concerning Quite a few variants have been examined for their possible association with ET. LINGO1 rs9652490 and STK32B rs10937625 appear to influence, to some extent, ET susceptibility. However, the conflicting results and the lack of replication for many candidate genes raise the need for collaborative multiethnic studies. Show less

Leucine-rich repeat and immunoglobin-domain containing (LRRIG) proteins that are commonly involved in protein-protein interactions play important roles in nervous system development and maintenance. LINGO-1, one of this family members, is characterized as a negative regulator of neuronal survival, axonal regeneration, and oligodendrocyte precursor cell (OPC) differentiation into mature myelinating oligodendrocytes. Three LINGO-1 homologs named LINGO-2, LINGO-3, and LINGO-4 have been described. However, their relative expression and functions remain unexplored. Here, we show by in situ hybridization and quantitative polymerase chain reaction that the transcripts of LINGO homologs are differentially expressed in the central nervous system. The immunostaining of brain slices confirmed this observation and showed the co-expression of LINGO-1 with its homologs. Using BRET (bioluminescence resonance energy transfer) analysis, we demonstrate that LINGO proteins can physically interact with each of the other ones with comparable affinities and thus form the oligomeric states. Furthermore, co-immunoprecipitation experiments indicate that LINGO proteins form heterocomplexes in both heterologous systems and cortical neurons. Since LINGO-1 is a promising target for the treatment of demyelinating diseases, its ability to form heteromeric complexes reveals a new level of complexity in its functioning and opens the way for new strategies to achieve diverse and nuanced LINGO-1 regulation. Show less

Essential Tremor (ET) is likely the most frequent movement disorder. In this review, we have summarized the current pharmacological options for the treatment of this disorder and discussed several future options derived from drugs tested in experimental models of ET or from neuropathological data. A literature search was performed on the pharmacology of essential tremors using PubMed Database from 1966 to July 31, 2019. To date, the beta-blocker propranolol and the antiepileptic drug primidone are the drugs that have shown higher efficacy in the treatment of ET. Other drugs tested in ET patients have shown different degrees of efficacy or have not been useful. Injections of botulinum toxin A could be useful in the treatment of some patients with ET refractory to pharmacotherapy. According to recent neurochemical data, drugs acting on the extrasynaptic GABAA receptors, the glutamatergic system or LINGO-1 could be interesting therapeutic options in the future. Show less

LINGO-1(LRR and Ig domain-containing NOGO receptor interacting protein 1) is a viable target for spinal cord injury (SCI) repair due to its potent negative regulation in neuron survival and axonal regeneration. Although promising, the intracellular mechanism underlying LINGO-1 regulation is unclear. Here, we identified miR-615 as a potential microRNA (miRNA) that directly targets LINGO-1 by binding its 3'-untranslated region (3'-UTR) and caused the translation inhibition of LINGO-1. MiR-615 negatively regulated LINGO-1 during neural stem cell (NSC) differentiation and facilitated its neuronal differentiation in vitro. Interestingly, compared to the control, neurons differentiated from miR-615-treated NSCs were immature with short processes. Further results showed LINGO-1/epidermal growth factor receptor (EGFR) signaling may be involved in this process, as blockade of EGFR using specific antagonist resulted in mature neurons with long processes. Furthermore, intrathecal administration of miR-615 agomir in SCI rats effectively knocked down LINGO-1, increased neuronal survival, enhanced axonal extension and myelination, and improved recovery of hindlimbs motor functions. This work thus uncovers miR-615 as an effective miRNA that regulates LINGO-1 in NSC and SCI animals, and suggests miR-615 as a potential therapeutic target for traumatic central nervous system (CNS) injury. Show less

LINGO1 is a transmembrane protein that is up-regulated in the cerebellum of patients with Parkinson's disease (PD) and Essential Tremor (ET). Patients with additional copies of the LINGO1 gene also present with tremor. Pharmacological or genetic ablation of large conductance Ca Show less

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (lingo-1) is selectively expressed on neurons and oligodendrocytes in the central nervous system and acts as a negative regulator in neural repair, implying a potential role in optic neuropathy. The aim of the present study was to determine whether adeno-associated virus serotype 2 (AAV2) vector-mediated transfer of lingo-1 short hairpin RNA Show less

The aim of this study was to investigate potential genetic overlap between essential tremor and Parkinson's disease in a cohort of 825 subjects from an Eastern Chinese population. A total of 441 Parkinson's disease patients and 384 healthy controls were recruited. The MassARRAY System was used to detect three essential tremor-related single nucleotide polymorphisms. Odds ratio (OR) and 95% confidential interval (CI) were calculated to assess the relationship between polymorphisms and Parkinson's disease susceptibility. Our results demonstrated that the odds ratios of rs3794087 of SLC1A2, rs9652490 of LINGO1, and rs17590046 of PPARGC1A were 0.71 (95% CI = 0.55-0.91), 0.99 (95% CI = 0.78-1.26), and 0.88 (95% CI = 0.62-1.25), respectively. An essential tremor SNP (rs3794087 of SLC1A2) is associated with a decreased risk of PD in the Eastern Han Chinese population, while rs9652490 (LINGO1) and rs17590046 (PPARGC1A) do not show an association. 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

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