title: Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain.
abstract: Synaptic impairment rather than neuronal loss may be the leading cause of cognitive dysfunction in brain aging. Certain small Rho-GTPases are involved in synaptic plasticity, and their dysfunction is associated with brain aging and neurodegeneration. Rho-GTPases undergo prenylation by attachment of geranylgeranylpyrophosphate (GGPP) catalyzed by GGTase-I. We examined age-related changes in the abundance of Rho and Rab proteins in membrane and cytosolic fractions as well as of GGTase-I in brain tissue of 3- and 23-month-old C57BL/6 mice. We report a shift in the cellular localization of Rho-GTPases toward reduced levels of membrane-associated and enhanced cytosolic levels of those proteins in aged mouse brain as compared with younger mice. The age-related reduction in membrane-associated Rho proteins was associated with a reduction in GGTase-Iβ levels that regulates binding of GGPP to Rho-GTPases. Proteins prenylated by GGTase-II were not reduced in aged brain indicating a specific targeting of GGTase-I in the aged brain. Inhibition of GGTase-I in vitro modeled the effects of aging we observed in vivo. We demonstrate for the first time a decrease in membrane-associated Rho proteins in aged brain in association with down-regulation of GGTase-Iβ. This down-regulation could be one of the mechanisms causing age-related weakening of synaptic plasticity.
authors.affiliation: Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Afshordel
authors.forename: Wellington Gibson
authors.initials: WG
authors.lastname: Wood
authors.forename: Urule
authors.initials: U
authors.lastname: Igbavboa
authors.forename: Walter E
authors.initials: WE
authors.lastname: Muller
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Eckert
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000523:psychology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D054022:Cerebrum / Q000378:metabolism*; D003072:Cognition Disorders / Q000209:etiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D017368:Protein Prenylation; D012333:RNA, Messenger / Q000096:biosynthesis; D013570:Synaptic Membranes / Q000378:metabolism*; D009435:Synaptic Transmission; D013729:Terpenes / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C547856:GGTI-2133; D007093:Imidazoles; D008565:Membrane Proteins; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D013729:Terpenes; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D020764:cdc42 GTP-Binding Protein; D020691:rab GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D007930:Leucine
keywords: aging; brain; isoprenoid; rho protein; small GTPases; synaptic markers