Association of VSNL1 with schizophrenia, frontal cortical function, and biological significance for its gene product as a modulator of cAMP levels and neuronal morphology

Abstract

We report an association of single-nucleotide polymorphisms (SNPs) for the VSNL1 gene (visinin-like 1) with schizophrenia and frontal cortical function in a sample of patients with Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) diagnoses of schizophrenia, compared with healthy controls. Moreover, VSNL1 SNPs were associated with performance in the Wisconsin Card Sorting Test, a measure for the assessment of frontal cortical function. The VSNL1 gene product, Visinin-like-protein-1 (VILIP-1), is a member of the neuronal EF-hand Ca2+-sensor protein family. Previously, VILIP-1 mRNA and protein expression were shown to be altered in animal models and in schizophrenia patients. VILIP-1 influences cytosolic cyclic adenosine mono phosphate (cAMP) levels, cell migration, exocytotic processes and differentiation in the periphery. This raises the question, whether, similar to other potential schizophrenia susceptibility genes such as Disc1, PDE4B and Akt, VSNL1 may affect cAMP signaling and neurite outgrowth in neurons. In dissociated rat hippocampal neurons, VILIP-1 small interfering RNA knockdown decreased cAMP levels and reduced dendrite branching, compared with control-transfected cells. In contrast, VILIP-1 overexpression had the opposite effect. Similar results have been obtained in the human dopaminergic neuronal cell line SH-SY5Y, where the effect on neurite branching and length was attenuated by the adenylyl cyclase inhibitor 2′,5′-dideoxyadenosine and the protein kinase A inhibitor KT5720. These results show that the association of VSNL1 SNPs with the disease and cognitive impairments, together with previously observed pathological changes in VILIP-1 protein expression, possibly occurring during brain development, may contribute to the morphological and functional deficits observed in schizophrenia.

Clozapine influences cytoskeleton structure and calcium homeostasis in rat cerebral cortex and has a different proteomic profile than risperidone

“…VILIP‐1 enhanced neurite outgrowth in SH‐SY5Y neuroblastoma via effects on cAMP signaling (Braunewell et al . ). But in another study, VILIP‐1 only slightly increased dendrite numbers and their over‐expression led to reduced axon outgrowth, whereas NCALD showed reduced dendrite numbers and branching (Yamatani et al .…”

“…Although there are some discrepancies in published results, VILIP‐1 level is rather reduced in schizophrenia (Braunewell et al . ). In a recent proteomic study, both VILIP‐1 and NCALD have been strongly suggested to be implicated in schizophrenia pathology (Wesseling et al .…”

Mutations that disrupt PHOXB interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma

“…The prototype member of the VSNL family, VILIP-1, was identified in a screen for developmentally regulated proteins that were upregulated during terminal differentiation of the nervous system (45) Moreover, overexpression of VILIP-1 in SH-SY5Y neuroblastoma cells causes an increase in the number and length of neurites (46). We report that PHOX2B-expressing neuroblastoma cells in which HPCAL1 was depleted exhibited markedly decreased neurite outgrowth compared to control shRNA-expressing cells.…”

Visinin-Like Protein-3 Modulates the Interaction Between Cytochrome b 5 and NADH-Cytochrome b 5 Reductase in a Ca2+-Dependent Manner

“…For example, examining how modulation of VILIP-1 and/or VILIP-3 expression may influence cognitive impairment may be worthy of further investigation. Interestingly, alterations in VILIP-1 expression have been shown to be associated with changes in the number of dendrites in neurons in schizophrenia [5]. In addition, VILIP has been evaluated as a biomarker in cerebrospinal fluid in mild cognitive impairment (MCI) [18].…”