title: Inhibiting geranylgeranylation increases neurite branching and differentially activates cofilin in cell bodies and growth cones.
abstract: Inhibitors of the mevalonate pathway, including the highly prescribed statins, reduce the production of cholesterol and isoprenoids such as geranylgeranyl pyrophosphates. The Rho family of small guanine triphosphatases (GTPases) requires isoprenylation, specifically geranylgeranylation, for activation. Because Rho GTPases are primary regulators of actin filament rearrangements required for process extension, neurite arborization, and synaptic plasticity, statins may affect cognition or recovery from nervous system injury. Here, we assessed how manipulating geranylgeranylation affects neurite initiation, elongation, and branching in neuroblastoma growth cones. Treatment with the statin, lovastatin (20 μM), decreased measures of neurite initiation by 17.0 to 19.0 % when a source of cholesterol was present and increased neurite branching by 4.03- to 9.54-fold (regardless of exogenous cholesterol). Neurite elongation was increased by treatment with lovastatin only in cholesterol-free culture conditions. Treatment with lovastatin decreased growth cone actin filament content by up to 24.3 %. In all cases, co-treatment with the prenylation precursor, geranylgeraniol (10 μM), reversed the effect of lovastatin. In a prior work, statin effects on outgrowth were linked to modulating the actin depolymerizing factor, cofilin. In our assays, treatment with lovastatin or geranylgeraniol decreased cofilin phosphorylation in whole cell lysates. However, lovastatin increased cofilin phosphorylation in cell bodies and decreased it in growth cones, indicating differential regulation in specific cell regions. Together, we interpret these data to suggest that protein geranylgeranylation likely regulates growth cone actin filament content and subsequent neurite outgrowth through mechanisms that also affect actin nucleation and polymerization.
authors: Center for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada.
authors: Filsy
authors: F
authors: Samuel
authors: Jairus
authors: J
authors: Reddy
authors: Radhika
authors: R
authors: Kaimal
authors: Vianey
authors: V
authors: Segovia
authors: Huanbiao
authors: H
authors: Mo
authors: DiAnna L
authors: DL
authors: Hynds
mesh_terms: D000818:Animals; D066146:Cell Body / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D051338:Cofilin 1 / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology*; D051381:Rats
chemical_list: D051338:Cofilin 1; D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; C017338:geranylgeraniol