53 A third gene found to be mutated in XLMR families is PAK3 54 PAK3 may well be a downstream effector of the Rho-GTPases Rac and Cdc42 putting the message forward to the actin cytoskeleton55 and to transcriptional activation. A subfamily of Rab-GTPases is also implicated in MR.56 Guanosine nucleotide

dissociation inhibitor-1 (GDI1) Inhibitors,research,lifescience,medical inhibits GDP dissociation from Rab3a by binding to GDP-bound Rab proteins and appears to be crucial in maintaining the balance between the GTP- and GDP-bound forms of Rab3. Rab3a is a small GTP-binding protein that functions in the recruitment of synaptic vesicles for exocytosis57,58 and is essential for long-term potentiation (LTP) in hippocampal neurons.59 All Inhibitors,research,lifescience,medical Rab proteins are hydrophobic by nature and need GDI to mediate membrane attachment and retrieval.60,61 Rab exists exclusively as a soluble complex with GDI in the cytoplasm, where it forms a reservoir to deliver Rab to the membrane during assembly of a transport vesicle. How might the biology of the small GTP-binding proteins explain human cognitive function? One possibility is that mutations disrupt the normal

development of axonal connections.62-64 This would fit with the known cell biology of the Rho-GTPases.65 Growth cones of developing axons find their way through the brain by sampling molecular signals, helped by GTPases.66 Whereas Cdc42 and Rac1 are involved in the formation Inhibitors,research,lifescience,medical of lamellipodia and filopodia,67 inhibition of Rho, Rac, and Cdc42 also reduces dendrite formation.68 Cognitive dysfunction could therefore be due to a Inhibitors,research,lifescience,medical failure to establish correct neuronal connections during CNS development. A second possibility is that synaptic function is compromised. This view is supported

by what is known about the function of Inhibitors,research,lifescience,medical Rab3a in exocytosis.69 Synaptic vesicles contain Rab3a, the most abundant Rab protein in the brain and, in one model, exocytosis leads to the dissociation of Rab3a from the vesicle.58 Since Rab3a-deficient mice have no fundamental deficits in synaptic vesicle exocytosis,57 the protein is not essential to the process, but is required to maintain too a normal reserve of synaptic vesicles. The GDI1 mutation, by disrupting Rab3a traffic, is expected to alter neurotransmitter release, which might, in turn, account for the intellectual impairment. Why is the effect of the mutation specific? Both the developmental and synaptic transmission account of Rho-GTPase involvement must explain why only neurones involved in cognitive systems are disrupted. One likely explanation is that the mutations only partly disrupt the brain system on which they operate, but it could also be that compensatory mechanisms, effective in other cell types, fail when it comes to neuronal processes involved in cognitive processing. Interestingly, there is also evidence that the cognitive defects associated with neurofibromatosis type 1 (NF1) derive from an effect on the Ras Trichostatin A solubility dmso pathway.