NRXN3
Neurexin-3 precursor (Neurexin III-alpha) (Neurexin-3-alpha) [C14orf60] [KIAA0743]
Publications[править]
Alzheimer disease (AD) is a common neurodegenerative disorder with distinct pathological features, with aging considered the greatest risk factor. We explored how aging contributes to increased AD risk, and determined concurrent and coordinate changes (including genetic and phenotypic modifications) commonly exhibited in both normal aging and AD. Using the Gene Expression Omnibus (GEO) database, we collected 1 healthy aging-related and 3 AD-related datasets of the hippocampal region. The normal aging dataset was divided into 3 age groups: young (20-40 years old), middle-aged (40-60 years old), and elderly (>60 years old). These datasets were used to analyze the differentially expressed genes (DEGs). The Gene Ontology (GO) terms, pathways, and function network analysis of these DEGs were analyzed. One thousand two hundred ninety-one DEGs were found to be shared in the natural aging groups and AD patients. Among the shared DEGs, ATP6V1E1, GNG3, NDUFV2, GOT1, USP14, and NAV2 have been previously found in both normal aging individuals and AD patients. Furthermore, using Java Enrichment of Pathways Extended to Topology (JEPETTO) analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we determined that changes in aging-related KEGG annotations may contribute to the aging-dependence of AD risk. Interestingly, [[NRXN3]], the second most commonly deregulated gene identified in the present study, is known to carry a mutation in AD patients. According to functional network analysis, [[NRXN3]] plays a critical role in synaptic functions involved in the cognitive decline associated with normal aging and AD. Our results indicate that the low expression of aging-related [[NRXN3]] may increase AD risk, though the potential mechanism requires further clarification.
MeSH Terms
- Adult
- Aged
- Aging
- Alzheimer Disease
- Down-Regulation
- Gene Expression
- Humans
- Middle Aged
- Nerve Tissue Proteins
- Polymorphism, Single Nucleotide
- Risk Factors
- Young Adult
Neurexins (NRXNs) are presynaptic terminal proteins and candidate neurodevelopmental disorder susceptibility genes; mutations presumably upset synaptic stabilization and function. However, analysis of human cortical tissue samples by RNAseq and quantitative real-time PCR at 8-12 postconceptional weeks, prior to extensive synapse formation, showed expression of all three NRXNs as well as several potential binding partners. However, the levels of expression were not identical; [[NRXN1]] increased with age and [[NRXN2]] levels were consistently higher than for [[NRXN3]]. Immunohistochemistry for each NRXN also revealed different expression patterns at this stage of development. [[NRXN1]] and [[NRXN3]] immunoreactivity was generally strongest in the cortical plate and increased in the ventricular zone with age, but was weak in the synaptogenic presubplate (pSP) and marginal zone. On the other hand, [[NRXN2]] colocalized with synaptophysin in neurites of the pSP, but especially with GAP43 and CASK in growing axons of the intermediate zone. Alternative splicing modifies the role of NRXNs and we found evidence by RNAseq for exon skipping at splice site 4 and concomitant expression of KHDBRS proteins which control this splicing. [[NRXN2]] may play a part in early cortical synaptogenesis, but NRXNs could have diverse roles in development including axon guidance, and intercellular communication between proliferating cells and/or migrating neurons.
MeSH Terms
- Aging
- Calcium-Binding Proteins
- Cell Adhesion Molecules, Neuronal
- Cerebral Cortex
- Embryonic Development
- Female
- Gene Expression Regulation, Developmental
- Humans
- Infant
- Male
- Nerve Tissue Proteins
- Neural Cell Adhesion Molecules
- Neurogenesis
- Tissue Distribution
Keywords
- cortical development
- neurexins
- neurodevelopmental disorders
- subplate