LRRC4 functions as a neuron-protective role in experimental autoimmune encephalomyelitis

Abstract

Background Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), belongs to the superfamily of LRR proteins and serves as a receptor for netrin-G2. LRRC4 regulates the formation of excitatory synapses and promotes axon differentiation. Mutations in LRRC4 occur in Autism Spectrum Disorder (ASD) and intellectual disability. Multiple sclerosis (MS) is a chronic neuroinflammatory disease with spinal cords demyelination and neurodegeneration. Here, we sought to investigate whether LRRC4 is involved in spinal cords neuron-associated diseases. Methods LRRC4 was detected in the CNS of experimental autoimmune encephalomyelitis (EAE) mice by the use of real-time PCR and western blotting. LRRC4−/− mice were created and immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35–55. Pathological changes in spinal cords of LRRC4−/− and WT mice 15 days after immunization were examined by using hematoxylin and eosin (H&E), Luxol Fast Blue (LFB) staining and immunohistochemistry. The number of Th1/Th2/Th17/Treg cells in spleens and blood were measured with flow cytometry. Differential gene expression in the spinal cords from WT and LRRC4−/− mice was analyzed by using RNA sequencing (RNA-seq). Adeno-associated virus (AAV) vectors were used to overexpress LRRC4 (AAV-LRRC4) and were injected into EAE mice to assess the therapeutic effect of AAV-LRRC4 ectopic expression on EAE. Results We report that LRRC4 is mainly expressed in neuron of spinal cords, and is decreased in the spinal cords of the EAE mice. Knockout of LRRC4 have a disease progression quickened and exacerbated with more severe myelin degeneration and infiltration of leukocytes into the spinal cords. We also first found that Rab7b is high expressed in EAE mice, and the deficiency of LRRC4 induces the elevated NF-κB p65 by up-regulating Rab7b, and up-regulation of IL-6, IFN-γ and down-regulation of TNF-α, results in more severe Th1 immune response in LRRC4−/− mice. Ectopic expression of LRRC4 alleviates the clinical symptoms of EAE mice and protects the neurons from immune damages. Conclusions We identified a neuroprotective role of LRRC4 in the progression of EAE, which may be used as a potential target for auxiliary support therapeutic treatment of MS.

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

“…LRRC4C encodes a post-synaptic adhesion molecule that binds with the conserved family of netrin G ligand (NGL) proteins (Choi et al, 2019) to regulate synaptic organization. There is no previous evidence that TRPS1 and LRRC4C interact to influence schizophrenia; however, LRRC4C has been implicated in brain disorders including schizophrenia, bipolar disorder, autism spectrum disorder, and developmental delay (Maussion et al, 2017; Zhang et al, 2021). Mouse models have shown that mice lacking NGL-1 exhibit hyperactivity and anxiolytic-like behavior due to widespread excitation of neurons in the brain.…”

Long noncoding RNA CCAT1 rs67085638 SNP contribution to the progression of gastric cancer in a Polish population

“…SNP rs6983267 has been shown to be located in the enhancer region of MYC, which plays a role in the regulation of CCAT1 expression 21 . Recently, it was demonstrated that the presence of the T allele of rs67085638 increased CCAT1 expression 22 . Moreover, CCAT1 expression correlated with BMI1 mRNA and protein levels in both GC cells in vitro and in vivo in murine tumour models 23 .…”

“…of patients M0 192 M1 22 Histological grading No. of patients G1 7 G2 66 G3 141 T tumour, N node, M metastasis, G grade 22 . a Age at first diagnosis.…”

“…Recent findings demonstrated that the presence of the minor allele of rs67085638 increased the expression of CCAT1 22 . Moreover, lncRNA CCAT1 knockdown significantly downregulated B-cell-specific Moloney leukaemia virus insertion site 1 (BMI1) mRNA in GC 23 .…”

Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

“…At the same time astrocytes2 is positive for Ubiquitin membrane protein transcripts UBB and UBC that control endocytic vesicle trafficking, SNCA, protein chaperons assisting in protein folding HSP90AA1, HSP90AB1, HSPA8, which suggest that this population may suffer from oxidative stress upon aggregation of unfolded αsynuclein. As a result, astrocytes2 shows high expression of JUN, FOS transcripts that suggest activation of apoptosis Astrocytes0 seems to be more resistant to PD: it is lost in PD in less significant numbers and has a high expression of markers linked to synapse growth and function SLC1A2 33 , LRRC4C 24 and VAV3 25…”