All ETDs from UAB

Advisory Committee Chair

Karl Heinz Braunewell

Advisory Committee Members

Jaideep Thottassery

Document Type

Thesis

Date of Award

2011

Degree Name by School

Master of Science (MS) School of Health Professions

Abstract

Background: 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 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, VILIP-1 may be associated with schizophrenia-related measures, and if it could mechanistically affect cAMP signaling and neurite outgrowth in neurons. Methods: 627 people with schizophrenia and 541 control subjects were ascertained and the genotyping was done. Wisconsin card sorting test, a measure for assessing impaired frontal cortical function, was performed in 352 control subjects and 213 schizophrenia patients. Primary hippocampal neurons and SH-SY-5Y cells were used to evaluate the potential mechanistic effect of VILIP-1 on neuronal differentiation. Results: We report an association of single nucleotide polymorphisms (SNPs) for the VSNL1 gene (visinin-like 1) with schizophrenia and frontal cortical function in two independent samples of patients with DSM IV diagnoses of schizophrenia and healthy controls. VSNL1 SNPs were associated with performance in the Wisconsin Card Sorting Test, a measure for the assessment of frontal cortical function. In dissociated rat hippocampal neurons VILIP-1 siRNA knockdown decreased cAMP levels and reduced dendrite branching compared to 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 DDA and the protein kinase A inhibitor KT5720. Conclusion: 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. Key words: VILIP-1, Schizophrenia, cAMP, SNP, Neuronal differentiation.

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