Emerging evidence implicating a role for neurexins in neurodegenerative and neuropsychiatric disorders

Abstract

Synaptopathies are brain disorders characterized by dysfunctional synapses, which are specialized junctions between neurons that are essential for the transmission of information. Synaptic dysfunction can occur due to mutations that alter the structure and function of synaptic components or abnormal expression levels of a synaptic protein. One class of synaptic proteins that are essential to their biology are cell adhesion proteins that connect the pre- and post-synaptic compartments. Neurexins are one type of synaptic cell adhesion molecule that have, recently, gained more pathological interest. Variants in both neurexins and their common binding partners, neuroligins, have been associated with several neuropsychiatric disorders. In this review, we summarize some of the key physiological functions of the neurexin protein family and the protein networks they are involved in. Furthermore, examination of published literature has implicated neurexins in both neuropsychiatric and neurodegenerative disorders. There is a clear link between neurexins and neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia. However, multiple expression studies have also shown changes in neurexin expression in several neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Therefore, this review highlights the potential importance of neurexins in brain disorders and the importance of doing more targeted studies on these genes and proteins.

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“…For example, for the schizophrenia-specific signature, the enriched pathways included ‘L1 cell adhesion molecule interactions ( Kurumaji et al , 2001 )’, ‘chaperone mediated autophagy ( Schneider et al , 2016 )’ and other relevant processes. The pathways linked to bipolar-specific signatures included several terms related to neuronal and synaptic processes, like ‘transmission across chemical synapses’ or ‘neurexins and neuroligins’, which have been related to psychotic disorders and in particular bipolar disorders ( Cuttler et al , 2021 ).…”

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“…Neuroligins are major post-synaptic adhesion molecules that interact with the neurexins, these occur in a very diverse range of alternatively spliced forms offering a large range of synaptic regulatory signals [ 304 ]. Mutations in genes encoding the neurexins and their ligands have been observed in neuropsychiatric disorders such as schizophrenia, autism, epilepsy, and Tourette syndrome, showing the neurexins have central roles to play in the control of synaptic plasticity [ 306 , 307 , 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 ]. HS-PGs have critical roles to play in the development of Alzheimer’s disease (AD) [ 317 ].…”

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“…Nlgs are postsynaptic CAMs that, in humans, are encoded by five genes ( NLG1 , NLG2 , NLG3 , NLG4 , and NLG4Y ), while, in mice, they are encoded by four genes ( Nlg1–4 ) [ 13 , 14 ]. Full-length Nlgs are composed of an N-terminal domain, an extracellular globular cholinesterase-like domain, a highly O-glycosylated stalk domain, a single-pass transmembrane helical domain, and a short C-terminal cytoplasmic tail terminating in sites for PDZ domain-binding [ 15 ] ( Figure 1 ).…”