Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein level in aged mouse brain

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 (23months) mice compared to younger (3months) 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, GGTaseI ss 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-I, which could contribute to age-related deficits in neuronal outgrowth.