Systemic or Forebrain Neuron-Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density

Abstract

Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-β deposition and neuroinflammation but only reduction in FT rescues cognitive function. The current study aimed to elucidate the potential mechanisms that may account for the lack of cognitive benefit in GGT-haplodeficient mice, despite attenuated neuropathology. The results showed that the magnitude of long-term potentiation (LTP) was markedly suppressed in hippocampal slices from GGT-haplodeficient mice. Consistent with the synaptic dysfunction, there was a significant decrease in cortical spine density and cognitive function in GGT-haplodeficient mice. To further study the neuron-specific effects of GGT deficiency, we generated conditional forebrain neuron-specific GGT-knockout (GGTCre+) mice using a Cre/LoxP system under the CAMKIIα promoter. We found that both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons were decreased in GGTCre+ mice compared with GGTCre- mice. Immunoblot analyses of cerebral lysate showed a significant reduction in cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras, in GGTCre+ mice, suggesting that insufficient geranylgeranylation of the Rho family of small GTPases may underlie the detrimental effects of GGT deficiency. These findings reinforce the critical role of GGT in maintaining spine structure and synaptic/cognitive function in development and in the mature brain.

Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer’s disease

“…Using a genetic approach, we have demonstrated recently that reduction of FTase, but not GGTase-I, ameliorates spatial learning and memory as well as attenuates Aβ deposition and neuroinflammation in APP/PS1 mice (Cheng et al, 2013). In a more recent study, we have observed that systemic or forebrain neuron specific deficiency of GGTase-I reduces dendritic spine density and impairs synaptic/cognitive function in wild type mice (Hottman et al, 2018), corroborating the critical role of GGTase-I and protein geranylgeranylation in neuronal structure and function suggested by previous studies (Gao, Yu, and Zhou, 2016; Zhou et al, 2008). These findings suggest that farnesylated and geranylgeranylated proteins play distinctive roles in the pathogenesis of AD.…”

Effects of 7,8-Dihydroxyflavone on Lipid Isoprenoid and Rho Protein Levels in Brains of Aged C57BL/6 Mice

“…We suggested that the downregulation of GGTase-Iβ may be one of the mechanisms that cause age-related weakening of synaptic plasticity (Afshordel et al 2014 ). Directly related to our findings Hottman et al recently published that systemic or forebrain neuron-specific deficiency of GGTase-I reduces dendritic spine density and impairs synaptic plasticity in the brains of young adult mice, concurrently with reduced geranylgeranylation of Rho proteins (Hottman et al 2018 ).…”

“…In vitro GGTase-I inhibition mimicked the changes we observed in the brain of aged mice, including a decreased frequency of synaptic markers (Afshordel et al 2014 ). That GGTase-I deficiency leads a significant decrease in cortical spine density and cognitive function has been recently shown in GGT-haplodeficient mice (Hottman et al 2018 ). Using a conditional forebrain neuron-specific GGT knockout they further demonstrated a decrease of both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons in those mice (Hottman et al 2018 ).…”

“…That GGTase-I deficiency leads a significant decrease in cortical spine density and cognitive function has been recently shown in GGT-haplodeficient mice (Hottman et al 2018 ). Using a conditional forebrain neuron-specific GGT knockout they further demonstrated a decrease of both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons in those mice (Hottman et al 2018 ). We have shown that the decrease in membrane-associated Rho proteins was unique to those proteins that are prenylated by the transferase GGTase-I, but not to Rab proteins prenylated by GGTase-II (Afshordel et al 2014 ).…”

“…This was confirmed in the current study. Accordingly, a significant reduction of cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras was demonstrated in mice harboring a conditional forebrain neuron-specific GGT-knockout (Hottman et al 2018 ). We observed elevated (geranylgeranylated) Rab3A protein levels in membrane preparations isolated from aged brain (Afshordel et al 2014 ).…”