Alteration of prenylation: Effect on neurite outgrowth and Rho GTPase signaling




Samuel, Filsy

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The action of the 3-hydroxy-3-methyglutaryl coenyzme A (HMG-CoA) reductase inhibitor, lovastatin, promotes neurite outgrowth in some systems and inhibits it in others (Schulz et al., 2004; Holmberg et al., 2006). Anecdotally, lovastatin also contradictorily relieves or exacerbates memory loss in Alzheimer's patients (Wagstaff et al., 2003; Sparks et al., 2008). We postulate that some of lovastatin effects are due to inhibition of prenylation precursors that alter Rho GTPase localization and loading of GTP. We show here that lovastatin decreases neurite initiation and concurrently increases GTP loading of RhoA in the cytosol and decreases GTP loading of Racl associated with the plasma membrane. We also assess how lovastatin affects the activity of cofilin, which is inactivated by phosphorylation by the common Rho GTPase effector, LIM kinase. We correlate cofilin phosphorylation with effects on actin filament content since cofilin is an actin depolymerizing agent. We use western blot analyses and immunocytochemistry to assess phosphorylated and total cofilin and find no significant deviations from control conditions. However, the amount of filamentous actin decreases in growth cones with lovastatin and lovastatin plus geranylgeraniol reversing this effect. Treatment with lovastatin increases GTP loading of RhoA in the cytosol fraction and decreases GTP loading of Rac1 in the membrane fraction. Together, these results suggest that lovastatin may promote actin depolymerization via Rho GTPases signaling leading to a decrease in the neurite initiation aspect of outgrowth. Elucidating the biochemical actions of lovastatin improves our understanding of how this treatment might mediate its effects in Alzheimer's disease and may facilitate the development of effective therapies for other nervous system disorders like traumatic brain or spinal cord injury.


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Biological sciences, Actin cytoskeleton, Lovastatin, Neurite outgrowth, Prenylation, Rho GTPase