Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are typically characterized by progressive neuronal loss and neurological dysfunctions in the nervous system, affecting both memory and motor functions. Neuregulins (NRGs) belong to the epidermal growth factor (EGF)-like family of extracellular ligands and they play an important role in the development, maintenance, and repair of both the central nervous system (CNS) and peripheral nervous system (PNS) through the ErbB signaling pathway. They also regulate multiple intercellular signal transduction and participate in a wide range of biological processes, such as differentiation, migration, and myelination. In this review article, we summarized research on the changes and roles of NRGs in neurodegenerative diseases, especially in AD. We elaborated on the structural features of each NRG subtype and roles of NRG/ErbB signaling networks in neurodegenerative diseases. We also discussed the therapeutic potential of NRGs in the symptom remission of neurodegenerative diseases, which may offer hope for advancing related treatment.
Gliomas, including brain lower grade glioma (LGG) and glioblastoma multiforme (GBM), are the most common primary brain tumors in the central nervous system. Neuregulin (NRG) family proteins belong to the epidermal growth factor (EGF) family of extracellular ligands and they play an essential role in both the central and peripheral nervous systems. However, roles of NRGs in gliomas, especially their effects on prognosis, still remain to be elucidated. In this study, we obtained raw counts of RNA-sequencing data and corresponding clinical information from 510 LGG and 153 GBM samples from The Cancer Genome Atlas (TCGA) database. We analyzed the association of NRG1-4 expression levels with tumor immune microenvironment in LGG and GBM. GSVA (Gene Set Variation Analysis) was performed to determine the prognostic difference of NRGs gene set between LGG and GBM. ROC (receiver operating characteristic) curve and the nomogram model were constructed to estimate the prognostic value of NRGs in LGG and GBM. The results demonstrated that NRG1-4 were differentially expressed in LGG and GBM in comparison to normal tissue. Immune score analysis revealed that NRG1-4 were significantly related to the tumor immune microenvironment and remarkably correlated with immune cell infiltration. The investigation of roles of m6A (N6-methyladenosine, m6A)-related genes in gliomas revealed that NRGs were prominently involved in m6A RNA modification. GSVA score showed that NRG family members are more associated with prognosis in LGG compared with GBM. Prognostic analysis showed that NRG3 and NRG1 can serve as potential independent biomarkers in LGG and GBM, respectively. Moreover, GDSC drug sensitivity analysis revealed that NRG1 was more correlated with drug response compared with other NRG subtypes. Based on these public databases, we preliminarily identified the relationship between NRG family members and tumor immune microenvironment, and the prognostic value of NRGs in gliomas. In conclusion, our study provides comprehensive roles of NRG family members in gliomas, supporting modulation of NRG signaling in the management of glioma.
Low-grade glioma (LGG), a heterogeneous tumour constituting up to approximately 20% of intracranial tumours, 1 is one of the most popular primary intracranial tumours in humans. LGG is classified by the World Health Organization (WHO) as grades I and II according to clinicopathological and histological features. 1 WHO grade I LGG is benign and discrete tumours that can be cured by surgical removal, and WHO grade II LGG is diffuse, infiltrative and rarely curable. 2 Most LGG cases occur in the fourth decade of life,
Neural cell adhesion molecular L1-like protein (CHL1) is a member of the cell adhesion molecule L1 family and serves an important role in the development and progression of tumors. The cytokine neuregulin 1 (NRG1) has been indicated in the tumorigenesis and promotion of metastasis through the modulation of L1. However, the roles of NRG1 in regulating CHL1 in glioma have not been elucidated. The present study investigated the protein expression levels and roles of CHL1 and the possible correlation between NRG1 and CHL1 protein expression levels in human gliomas, both in vivo and in vitro. Using immunohistochemistry coupled with a human glioma tissue microarray, it was demonstrated that the percentage of CHL1-positive areas was the highest in grade II glioma tissues. Using immunofluorescence staining, a positive correlation was identified between the expression levels of CHL1 and proliferating cell nuclear antigen. In addition, CHL1 downregulation also resulted in increased senescence of U-87 MG human glioblastoma cells. In vitro, administration of NRG1α induced a significant increase in CHL1 protein expression levels in human glioma SHG-44 and U251 cells and in human glioblastoma U-87 MG cells, whereas NRG1β failed to increase CHL1 expression levels in U251 cells. These findings were further confirmed by the downregulation of NRG1 expression levels using small interfering RNA treatment, which resulted in the reduction of CHL1 protein expression levels in U-87 MG cells. These data indicate that NRG1 can regulate CHL1 protein expression levels in gliomas, that it is correlated with malignancy, and that NRG1 may contribute to malignancy by upregulating CHL1 protein expression levels in glioma/glioblastoma cells.
Alzheimer’s disease (AD) is a neurodegenerative disorder that occurs mainly in the elderly and presenile life stages. It is estimated that by the year 2050, 135 million people will be affected by AD worldwide, representing a huge burden to society. The pathological hallmarks of AD mainly include intracellular neurofibrillary tangles (NFTs) caused by hyperphosphorylation of tau protein, formation of extracellular amyloid plaques, and massive neural cell death in the affected nervous system. The pathogenesis of AD is very complicated, and recent scientific research on AD is mainly concentrated on the cortex and hippocampus. Although the spinal cord is a pivotal part of the central nervous system, there are a limited number of studies focusing on the spinal cord. As an extension of the brain, the spinal cord functions as the bridge between the brain and various parts of the body. However, pathological changes in the spinal cord in AD have not been comprehensively and systematically studied at present. We here review the existing progress on the pathological features of AD in the spinal cord.
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