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Impaired geranylgeranyltransferase‐I regulation reduces membrane‐associated Rho protein levels in aged mouse brain
Author(s) -
Afshordel Sarah,
Wood Wellington Gibson,
Igbavboa Urule,
Muller Walter E.,
Eckert Gunter P.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12654
Subject(s) - prenylation , neurodegeneration , gtp' , cytosol , biology , rab , microbiology and biotechnology , synaptic plasticity , membrane protein , biochemistry , gtpase , endocrinology , medicine , membrane , enzyme , receptor , disease
Synaptic impairment rather than neuronal loss may be the leading cause of cognitive dysfunction in brain aging. Certain small Rho‐ GTP ases are involved in synaptic plasticity, and their dysfunction is associated with brain aging and neurodegeneration. Rho‐ GTP ases undergo prenylation by attachment of geranylgeranylpyrophosphate ( GGPP ) catalyzed by GGT ase‐I. We examined age‐related changes in the abundance of Rho and Rab proteins in membrane and cytosolic fractions as well as of GGT ase‐I in brain tissue of 3‐ and 23‐month‐old C57 BL /6 mice. We report a shift in the cellular localization of Rho‐ GTP ases 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 GGT ase‐Iβ levels that regulates binding of GGPP to Rho‐ GTP ases. Proteins prenylated by GGT ase‐ II were not reduced in aged brain indicating a specific targeting of GGT ase‐I in the aged brain. Inhibition of GGT ase‐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 GGT ase‐Iβ. This down‐regulation could be one of the mechanisms causing age‐related weakening of synaptic plasticity.Rho‐GTPases are geranylgeranylated by transferase GGTase‐I. Their prenylation is essential for their localization in membranes, the site of their activation and function. Despite elevated GGPP levels in brains of aged (23 months) mice compared to younger (3 months) mice as well as in GGTI‐2133‐treated SH‐SY5Y cells, the amount of total (homogenate) Rho‐GTPases (Rac1, RhoA, and Cdc42) was unchanged. Treatment with the GGTaseI‐inhibitor GGTI‐2133 decreased prenylation of Rho‐GTPases in membrane preparations of aged mice and SH‐SY5Y, correlating with the reduction of relative GGTase activity, GGTaseIß protein, and mRNA levels. As Rac1, RhoA, and Cdc42 are associated with synaptogenesis, we examined the synaptic marker proteins GAP43 and synaptophysin. GAP43 and synaptophysin declined in an age‐related manner in the mouse brain and were also reduced in our in vitro model. Faulty regulation of Rho proteins in aged brain is associated with a specific deficit in GGTase‐Iβ, which could contribute to age‐related deficits in neuronal outgrowth.