Genetics of alcohol use disorders: Actin gets into the act

Actin is the most common intracellular protein in eukaryotic cells, with estimates for nonmuscle cells generally ranging from 1–5% of cellular protein (1). Until fairly recently, actin was widely regarded as a ubiquitous and rather humdrum molecule. However, accumulating research is increasingly pointing to a crucial role of impaired actin dynamics in central nervous system pathologies and, in particular, those related to aging and neurodegeneration. The study by Ojelade et al. (2) adds an exciting new angle to this emerging field. In a series of elegant experiments using mutant flies, the authors show that the gene-encoding Ras suppressor 1 (Rsu1) acts upstream of Rac1 and is required in the adult nervous system for regular ethanol sensitivity. Moreover, using macrophage-like Drosophila Schneider S2 cells, the authors show that knockdown of Rsu1 as well as constitutive overexpression of Rac1 causes robust decreases in the ratio of globular:filamentous actin. It may be worthwhile to ascertain whether a similar shift toward increased rigidity of the actin network also occurs in the nervous system of flies with a disruption of Rsu1. Of note, compensatory changes in other actin-binding proteins have been described in the brains of mice lacking actin-severing protein gelsolin (3). Interestingly, the mechanisms through which increased stability of the actin cytoskeleton promotes neurodegeneration and reduced sensitivity to ethanol-induced sedation likely show considerable overlap. We have previously demonstrated that an impairment in actin depolymerization interferes with the rundown of activated NMDA receptors and voltage-dependent Ca²⁺ channels, and thereby exacerbates neuronal injury following brain ischemia. Furthermore, actin filament stabilization in gelsolin-deficient synaptosomes increased depolarization-induced intracellular Ca²⁺ levels and enhanced exocytotic neurotransmitter release, which could be reversed by actin disruptor cytochalasin D (3, 4). Conversely, ethanol has been demonstrated to promote actin depolymerization in cerebellar granule neurons (5). In addition, neurons lacking Eps8, another important regulator of actin dynamics, show increased NMDA currents and enhanced NMDA receptor activity after ethanol exposure and Eps8-KO mice demonstrate increased ethanol consumption (5). Finally, Ojelade et al. report that, in humans, polymorphisms in Rsu1 are associated with brain activation in the ventral striatum during reward anticipation and with alcohol consumption (2). Taken together, these findings indicate that the dynamic state of the actin meshwork plays a key role in mediating ethanol preference. Accordingly, biological parameters related to actin dynamics deserve to be explored as potential markers of increased risk of alcohol use. The actin cytoskeleton may even prove useful as a novel target for pharmacological interventions in alcohol use disorders.