Protein prenylation, synaptic function and agins

• Autorzy: Afshordel S. , Eckert G.P. , Hortman D.A. , Li L. , Igbavboa U. , Wood W.G.
• Języki publikacji: EN

Abstrakty

EN

Synaptic plasticity is the cellular basis of learning and memory that declines with increasing age. Dendritic structure plays a key role in synaptic plasticity that is impaired in aged brain. Rho family small GTPases, including Rac1 and RhoA play distinct roles in the development and modification of dendritic spines, axons and synapses. We recently found that levels of prenylated Rac1 and RhoA were significantly lower in aged mouse brain as compared with younger mice. This reduction was associated with a decrease in abundance of the synaptic markers synaptophysin and GAP43. Rac1 stimulates spine formation and RhoA impedes spine formation. Previous studies have proposed that there needs to be a balance in the activity of those proteins for optimal spine function. This balance appears to be disrupted in aged brain which could contribute to age-related spine dysfunction. Rac1 and RhoA, are prenylated by GGTase-I whereas Rab proteins are prenylated by GGTase-II. Prenylated Rab protein levels were similar in the young and aged mice raising the possibility that the lower Rho-GTPase prenylated protein levels were the result of a deficiency in GGTase-I. We found that mRNA and protein levels of GGTase-Iβ were significantly lower in brain tissue of aged mice as compared with younger mice. Further support for the critical role of GGTase-I in synaptic plasticity comes from two novel mouse models: (1) a heterozygous GGTase-Iβ gene knockout; and (2) a homozygous floxed GGTase-Iβ brain neuron specific Cre recombinase. Data from those mice revealed diminished long-term potentiation in the CA1 region of the hippocampus and loss of dendritic spines. We propose that impaired GGTase-Iβ regulation in aged brain causes a reduction in Rac1 and RhoA protein prenylation resulting in disruption of the dynamic balance between those proteins. That disruption triggers aberrant downstream effector function causing a loss of synaptic plasticity and impaired cognitive function.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2015
• Tom: 75
• Numer: Supl.
• Opis fizyczny: p.S14-S15

Twórcy

autor

Afshordel S.

• Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, Germany

autor

Eckert G.P.

• Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, Germany

autor

Hortman D.A.

• Department of Experimental and Clinical Pharmacology, School of Medicine, University of Minnesota, Minneapolis, MN, USA

autor

Li L.

• Department of Experimental and Clinical Pharmacology, School of Medicine, University of Minnesota, Minneapolis, MN, USA

autor

Igbavboa U.

• Department of Pharmacology, School of Medicine, University of Minnesota, Minneapolis, MN, USA

autor

Wood W.G.

• Department of Pharmacology, School of Medicine, University of Minnesota, Minneapolis, MN, USA