## 3 Discussion
Prosurvival activity was demonstrated for GGOH when this non-sterol isopenoid was added to ATR-, SIM- or M\(\beta\)CD-treated cells irrespective of inserted gene (Figure 2). Noticeably, GGOH prevented ATR cytotoxicity better than in SIM or M\(\beta\)CD treatments (Figure 2, \(p\) < 0.01-0.001), showing that protein prenylation with geranylgeraniol might be more impaired by ATR than SIM. Actually, several studies highlight the physiological significance of geranylgeranylation catalyzed by two types of enzymes (GGTase-I liable for monogeranylgeranylation, and GGTase-II that catalyzes digeranylgeranylation of sGTPases) [45; 46]. The aforementioned effect of GGOH in PC-12 neuronal cells looks a lot like that described by us recently in C2C12 mouse myoblasts [47]. Neuronal survival is diminished by statins; moreover, statin effect is independent of reduced cholesterol level, since neuronal viability is restored by FPP/GGPP supplementation, and not by adding cholesterol [48]. Importantly, the long-term potentiation (LTP) known as long-lasting strengthening of synapses between nerve cells could be blocked with statins [49]. As a result, long-term memories are fully dependent on the MEV pathway and geranylgeraniol, but cholesterol is not able to reverse the LTP blockade [50]. For more details about links between the MEV pathway and AD see the papers [4; 5; 6; 7]. In a similar way to our cell viability study, GGOH-dependent prenylation was demonstrated to increase neuronal dendritic outgrowth and dendritic protrusion density, as well as increased synaptic proteins in crude synaptosomal fractions [43]. By all means, the MEV pathway with GGOH preserve neuronal functions because prenylation of some sGTPases mediated by GGTase-I seems to maintain cognitive functions [51]. Since incubation with FOH alike GGOH prevented ATR-induced toxicity (Figure 2E) we admit FOH could contribute to GGOH production. It is plausible to expect FOH in the non-sterol pathway as the GGOH synthesis in neurons is favored over squalene [52]. Additionally, examination of gene expression patterns points to lower activity of the pre-squalene pathway in neurons [53], which favors the non-sterol MEV pathway, giving rise to FPP, GGPP, ubiquinone, dolichol or heme A. Altogether, these data and recalled reports advocate boosted non-sterol branch of the MEV pathway in neurons, probably owing to the prenylation of sGTPases [54]. In muscle cells we found that sGTPase RAP1 is a good candidate to control cell viability during myogenesis from C2C12 mouse myoblasts [47]. It should be pointed out that regardless of a possible shutdown, the branch of squalene synthesis remains vital to neurons, as plasma membrane nanodomains (lipid rafts, LR) with its cholesterol and sphingolipids control cell signaling and protein processing [55]. Currently, several novel pathways are indicated in AD pathogenesis, including sGTPases. These proteins have been implicated as critical components in AD pathogenesis, although their cognate targets in AD remain obscure. Binding GTP activates sGTPases, while inactivation is achieved by GDP. Regulatory proteins regulate GDP/GTP exchange in sGTPases. The guanine nucleotide exchange factors (GEFs) support GTP bound state (activation) whereas GTPase activating proteins (GAPs) preserve GDP bound state (inactivation). A\(\beta\)PP and A\(\beta\) expression levels have been shown to increase in response to active sGTPases [56; 57]. As sGTPases are not transmembrane proteins they require addition of FOH or GGOH at their C termini for normal GTPase function [54]. In contrast to M\(\beta\)CD, which depletes just plasma cholesterol, statins in turn lower the concentrations of FPP and GGPP, despite their cholesterol lowering effect. As a result, treatment with statins additionally inhibits the membrane anchorage of sGTPases and A\(\beta\)PP processing to A\(\beta\)PP C-terminal fragments and A\(\beta\) in neuroblastoma cells [57].