The neurexins are part of a synaptic adhesion proteins family. Their work is to bind neuroligins to form Ca(2+)-. The body depends on neurexin/neuroligin for various works at synapses so that the central nervous system can function properly. The paralogous genes that play a vital role in synaptic formation and maintenance encode them. The complex relationships are important because of the efficiency in neurotransmission. It also leads to the formation of synaptic contacts. Each gene is transcribed in neurons from two independent promoters to yield longer (a) and shorter (b) proteins that are composed of distinct extracellular domains linked to identical intracellular sequences. The description of neurexin 1 and its role in the development of Schizophrenia is crucial.
Neurexin-1-alpha is a type of protein found in the human body. The protein is part of the NRXN1 gene. Neurexins belong to the family of proteins. Their work is to do cell adhesion in the molecules and receptors. The unlinked genes encode several of them (Bang & Owczarek 2013). They are the largest of the other genes. The three genes typically use two alternate promoters. They have other joined exons. Part of their work is to produce mRNA transcripts in plenty. They also generate protein isoforms. The three members can create more than two thousand variants. They use two alternative promoters. The promoters are the alpha and the beta. They also extensively splice in each family member (Shen et al. 2015).
The upstream promoters produce most of the transcripts. They instruct the alpha-neurexin isoforms (Shen et al. 2015). The numbers of transcripts that come from the downstream promoter are small and mainly encode beta-neurexin isoforms (Nelson, Fairclough & Archer 2009). The alpha-neurexins usually have epidermal growth. They also display and interact with neurexophilin. The beta-neurexins do not comprise the EGF-like progressions. The alpha-neurexins have enough laminin G domains. The beta-neurexins do not have such domains. A third promoter called the gamma was also identified for this gene in the 3′ region (Kirov et al. 2009).
The gene mainly attaches to it as a single copy on the short arm of the chromosome known as 2 (2p 16.3). It has a base length of approximately 1million bases. It lies on the Crick strand and encodes a protein of about one thousand amino acids. It has a molecular weight of 161.883 kDa.
It has mutations that interrupt its expressions and is mainly the cause of Schizophrenia, intellectual disability, and autism (Howell & Pillai 2014). It interacts with NLGN1. The neurexin genes use alternative promoters. They include splice sites and exons. They are critical for encoding potentially hundreds or thousands of mRNA transcripts (Wang 2016).
After intensive study over the years, there have been several suggestions that neurexin 1 causes Schizophrenia. The submicroscopic chromosomal deletions disrupt the gene neurexin 1. The action causes or increases the risk of developing schizophrenia (Wright & Washbourne 2011). There has been a comprehensive review of the structure and possible function of NRXNs and NLGNs (Owczarek, Bang & Berezin 2015).
Vertebrate NRXNs and NLGNs are adhesion molecules. They have a distinct synaptic function that is not in other molecules (Wright & Washbourne 2011). The available studies prove that NRXNs and NLGNs work together. One of the primary purposes is to reconcile critical communications between presynaptic and postsynaptic specializations (Martinelli & Südhof 2011).
Other studies that include the cell culture and the mouse knockouts indicate that the molecules provide critical synapse function in the entire service. But they are not for synapse formation. They influence trans-synaptic activation of synaptic transmission; and their dysfunction impairs the properties of synapses and disrupts neural networks without completely abolishing synaptic transmission (Reichelt, Rodgers & Clapcote 2012).
The 3 NRXN genes each encode an alpha (α) protein and a beta (β) protein from independent promoters (Dawson et al. 2012). NRXNs comprise a remarkable molecular diversity. The RNA messenger can be a result of other organs and genes joining to produce many unique protein isoforms (Khurana & Lindquist 2010). Deletions in the NRXN1 gene have led to numerous problems in the human body. One of the challenges includes mental retardation. There is also the issue of delays in mental development. Some studies have reported NRXN1 deletions in cases with schizophrenia (Rubin, Trawver & Springer 2013).
The first suggestion that NRXN1 deletions might confer risk of schizophrenia came from a study by Kirov and his scientific laboratory colleagues (Dagher 2010). They used array comparative genome hybridization (array-CGH) to screen the genomes of about ninety cases of schizophrenia they had recruited in Bulgaria (Knight, Xie & Boulianne 2011). They also had approximately 35 000 probes for chromosomal copy number variants (CNVs) at a resolution of about 80 000 bp. During the research, the destruction of NRXN1 was found in the female organs. She had a brother who also had the same condition. It affected the promoter and the first exon of the gene (Knight, Xie & Boulianne 2011). In the study, both of them did not have signs of pre-morbid cognitive problems. Their dysmorphic features were also in good order. Removal of NRXN1 was not available for viewing in most of the subjects. However, there were successful discoveries that indicated that NRXN1 deletions also led to the development of autism.
There was also one deletion in a subject with mental retardation. The authors hypothesized that deletions in this gene might confer risk to schizophrenia as well as to other neurodevelopment disorders (Khurana & Lindquist 2010). They also found a de novo duplication of 1.4Mb of chromosome 15. The chromosome had a protein-binding gene that relayed a protein known as Mint2 (Reissner, Runkel & Missler 2013).
One of the interesting discoveries came from the International Schizophrenia Consortium (Gareeva et al. 2015). From their study, they found four deletions in about three thousand three hundred cases. There were also three in about three thousand controls from some European countries. Sweden and the UK were part of the countries (Eacker, Dawson & Dawson 2010). There were no duplications.
When using array-CGH, there are identical report twins with early-onset schizophrenia who shared a 115-kb deletion in the gene (disrupting exons in the 3′ end) among a total of 233 schizophrenia cases and 268 controls (Dachtler et al. 2015). There have been numerous studies in this area. Most of the findings suggest that the deletions of NRXN1 have been leading to an increase in the risk of schizophrenia.
However, the analysts give a degree of caution that not all cases develop into Schizophrenia (Roth, Rauscher & Archer 2009).
There is a need for more studies to be conducted in the context of establishing the relationship between the condition and the gene mutations. There have been some difficulties in the research programs. For instance, detecting CNS of different sizes was also a major challenge for the researchers. The risk of schizophrenia increases due to the growth of CNVs. The doctors and specialists in the field of study that involves neurexin should continue delving into this area extensively. Perhaps by doing so, they might discover better treatment for schizophrenia and other ailments.
Bang, M & Owczarek, S 2013, A matter of balance: role of neurexin and neuroligin at the synapse, Neurochem Res, vol. 38, no. 6, pp.1174-1189.
Dachtler, J, Ivorra, J, Rowland, T, Lever, C, Rodgers, R & Clapcote, S 2015, Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia, Behavioral Neuroscience, vol. 129, no. 6, pp.765-776.
Dagher, A 2010, The role of environmental factors, Schizophrenia Research, vol. 117, no. 2-3, p.136.
Dawson, N, Thomson, D, Morris, B & Pratt J 2012, Poster #14 neural systems underlying schizophrenia-related behavioral phenotypes in mice, Schizophrenia Research, vol. 136, no. 5, p.S96.
Eacker, S, Dawson, T & Dawson, V 2010, Understanding microRNAs in neurodegeneration, Nature Reviews Neuroscience, vol. 20, no. 2, p.25.
Gareeva, A, Traks, T, Koks, S & Khusnutdinova, E 2015, The role of neurotrophins and neurexins genes in the risk of paranoid schizophrenia in Russians and Tatars, Russ J Genet, vol. 51, no. 7, pp.683-694.
Howell, K & Pillai, A 2014, Effects of prenatal hypoxia on schizophrenia-related phenotypes in heterozygous reeler mice: a gene×environment interaction study, European Neuropsychopharmacology, vol. 24, no. 8, pp.1324-1336.
Khurana, V & Lindquist, S 2010, Modelling neurodegeneration in saccharomyces cerevisiae: why cook with baker’s yeast?, Nature Reviews Neuroscience, vol. 11, no. 6, pp.436-449.
Kirov, G, Rujescu, D, Ingason, A, Collier, D, O’Donovan, M & Owen, M 2009, Neurexin 1 (NRXN1) deletions in schizophrenia, Schizophrenia Bulletin, vol. 35, no. 5, pp.851-854.
Knight, D, Xie, & Boulianne, G 2011, Neurexins and neuroligins: recent insights from invertebrates, Molecular Neurobiology, vol. 44, no. 3, pp.426-440.
Martinelli, D & Südhof, T 2011, Cerebellins meet neurexins (commentary on matsuda & yuzaki), European Journal of Neuroscience, vol. 33, no. 8, pp.1445-1446.
Nelson, L, Fairclough, J & Archer, C 2009, Use of stem cells in the biological repair of articular cartilage, Expert Opinion on Biological Therapy, vol. 10, no. 1, pp.43-55.
Owczarek, S, Bang, M & Berezin, V 2015, Neurexin-neuroligin synaptic complex regulates schizophrenia-related DISC1/Kal-7/Rac1 “signalosome”, Neural Plasticity, vol. 20, no. 1, pp.1-8.
Reichelt, A, Rodgers, R & Clapcote, S 2012, The role of neurexins in schizophrenia and autistic spectrum disorder, Neuropharmacology, vol. 62, no. 3, pp.1519-1526.
Reissner, C, Runkel, F & Missler, M 2013, Neurexins. Genome Biol, vol. 14, no. 9, p.213.
Roth, R, Rauscher, M & Archer, A 2009, Selectivity in binary fluid mixtures: static and dynamical properties, Physical Review E, vol. 80, no. 2, p. 35.
Rubin, A, Trawver, K & Springer, D 2013, Psychosocial treatment of schizophrenia, Wiley, Hoboken, New Jersey.
Shen, H, Chen, Z, Wang, Y, Gao, A, Li, H, Cui, Y, Zhang, L, Xu, X, Wang, Z & Chen, G 2015, Role of neurexin-1β and neuroligin-1 in cognitive dysfunction after subarachnoid hemorrhage in rats, Stroke, vol. 46, no. 9, pp.2607-2615.
Wang, H 2016, Endocannabinoid mediates excitatory synaptic function of β-neurexins. commentary: β-neurexins control neural circuits by regulating synaptic endocannabinoid signaling, Front. Neurosci, vol. 10, no. 5, pp.200-201.
Wright, G & Washbourne, P 2011, Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy, Journal of Neurochemistry, vol. 117, no. 5, pp.765-778.