PRIMARY CELL CULTURE ANALYSES OF STATIN-INDUCED TOXICITY IN DROSOPHILA NEURONS

picture of Monica Chaung presenting his/her poster: PRIMARY CELL CULTURE ANALYSES OF STATIN-INDUCED TOXICITY IN DROSOPHILA NEURONS

Monica Chaung , Robert Kraft, Linda L. Restifo

PRIMARY CELL CULTURE ANALYSES OF STATIN-INDUCED TOXICITY IN DROSOPHILA NEURONS

Statins, a profitable class of cholesterol-lowering drugs that significantly reduce the risk of heart attacks and stroke, are taken by ~15 million Americans. Despite their benefits, statins can cause negative side effects, of which the best known is muscle damage (myopathy). Recently the Food and Drug Administration added transient cognitive impairment to the warning labels on statins. Understanding which individuals are at greater risk for statin-induced memory loss will help physicians decide which patients should be prescribed statins. When exposed to statins, Drosophila brain neurons in primary culture exhibit reduced neurite outgrowth and the “beads-on-a-string” (BOS) defect. I assessed the recovery of neurite outgrowth upon statin removal from wild-type neuronal cultures prepared from the developing central nervous system. Neurons incubated in 15.0-μM pravastatin for 1.5 days in vitro (div) and given fresh media with no pravastatin showed significantly greater total neurite length, branch number, and territory at 3 div than neurons grown with statin throughout. These results confirm qualitative observations that statin-induced effects on neurite outgrowth are reversible. One advantage of studying statin neurotoxicity in Drosophila is that insects must obtain cholesterol through their diet. Therefore, the statin-induced abnormalities of neuronal growth and morphology in this genetic model organism cannot be due to reduced cholesterol synthesis. Rather, statin’s inhibition of HMG-CoA (3-hydroxy-3-methyl-glutaryl-Coenzyme A) reductase must be impacting other downstream pathways, perhaps by affecting function of small GTPases, which are essential for brain development and synaptic plasticity. To investigate genetic effects on statin sensitivity, I analyzed fragile X-mutant neurons. These mutants are known to have increased levels of the small GTPase Rac and thus might show lower statin sensitivity. Neurons cultured from dissociated brains of developing fragile X-mutants and wild-type controls were grown for 3 div with 0.0 μM, 7.5 μM or 15.0 μM pravastatin. I focused on gamma mushroom body neurons because of their well-known importance in learning and memory. At 15.0 μM pravastatin, total neurite length, total and higher-order branch number, and territory of mutant neurite arbors were significantly smaller than those of control neurons. Hence, fragile X-mutant neurons demonstrated greater statin sensitivity. Supported by the Neurology Stroke Research Fund and the UA Provost's Office.

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