Abstract
Recent reports suggest abnormalities in the regulation of actin cytoskeletal dynamics in schizophrenia, despite consistent evidence for normal actin expression. We hypothesized that this may be explained by changes in the polymerization state of actin, rather than in total actin expression. To test this, we prepared filamentous actin (F-actin, polymeric) and globular actin (G-actin, monomeric) fractions from postmortem anterior cingulate cortex from 16 patients with schizophrenia and 14 comparison subjects. Additionally, binding of fluorescently-labeled phalloidin, a selectively F-actin-binding peptide, was measured in unfractionated samples from the same subjects. Western blot analysis of fractions revealed decreased F-actin, increased G-actin, and decreased ratios of F-actin/total actin and F-actin/G-actin in schizophrenia. Decreased phalloidin binding to F-actin in parallel experiments in the same subjects independently supports these findings. These results suggest a novel aspect of schizophrenia pathophysiology and are consistent with previous evidence of reduced dendritic spine density and altered synaptic plasticity in schizophrenia, both of which have been linked to cytoskeletal abnormalities.
Highlights
While the etiology of schizophrenia is not established, a consistent finding in schizophrenia brain is reduced dendritic spine density and altered spine morphology[1,2,3,4]
Consistent with this hypothesis, many proteins crucial to stabilization of the actin cytoskeleton have been shown to be abnormally expressed in schizophrenia, including reelin, fragile X mental retardation protein, disrupted in schizophrenia-1 (DISC-1), cell division cycle protein 42 (CDC42), and Duo[6,7,8,9]
We measured phalloidin binding in prepared fractions to validate the enrichment of filamentous actin in the F-actin/ β-tubulin G-actin/ β-tubulin Phalloidin (F-actin) fraction, and to confirm depletion of F-actin binding in the G-actin fraction
Summary
While the etiology of schizophrenia is not established, a consistent finding in schizophrenia brain is reduced dendritic spine density and altered spine morphology[1,2,3,4]. One hypothesis implicates dysfunction of the actin cytoskeleton, the stabilization of which is essential for maintaining dendritic spine morphology and density[5] Consistent with this hypothesis, many proteins crucial to stabilization of the actin cytoskeleton have been shown to be abnormally expressed in schizophrenia, including reelin, fragile X mental retardation protein, disrupted in schizophrenia-1 (DISC-1), cell division cycle protein 42 (CDC42), and Duo[6,7,8,9]. These abnormalities are intriguing, given multiple reports of normal actin protein expression in schizophrenia brain[10, 11]. Underlying this rearrangement of actin is the dynamic polymerization of actin from its monomeric form
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