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  • In addition of being key mediators of actin


    In addition of being key mediators of Salvinorin A dynamics in neurons, PAKs have been recently found to regulate cell motility and gene transcription in inflammatory cells. In this regard, group I PAK activation and consequent cytoskeletal remodeling events occur upon stimulation of neutrophils, while treatment with the pharmacological PAK inhibitor, PF3758309, impairs neutrophil activation, morphological polarization and directional migration [78], suggesting a role for PAK1 in promoting the structural reorganization of the cell required for chemotactic processes during an inflammatory response. PAK1 activation has also been associated with intestinal inflammation by promoting the transcriptional activity of NF-κB, the master regulator of pro-inflammatory genes [79], [80]. Similarly, PAK4 is activated in human astrocytes upon viral infection and PAK4 can mediate the activation of ERK-NF-κB pathway in these cells [52]. Additionally, PAK4 is implicated in the activation of AP-1, another transcriptional factor responsible for the expression of inflammatory cytokines [52]. Based on these observations, PAKs emerge as key kinases in the regulation of neuronal functions, with possible implications in the activation of inflammation responses in glial cells.
    PAKs in neurodegeneration: loss- or gain- of function? Compelling evidence indicate that PAKs are implicated in NDs (e.g. AD, HD and PD). This is not surprising considering their high expression levels in the CNS and the participation in a variety of signaling pathways that regulate brain physiology. Both loss- and gain- of PAK kinase activity has been detected in human post-mortem brains and mouse models of NDs suggesting that a fine tuning of PAK enzymatic activity are required to maintain brain homeostasis (Fig. 3B and Table 1). The first indication that PAKs level and activity are altered in NDs came from a study in human post-mortem AD brains (temporal cortex and hippocampus) [32]. AD is characterized clinically by progressive cognitive decline and pathologically by prodromal accumulation of extracellular plaques containing amyloid-β (Aβ) protein and intracellular neurofibrillary tangles containing tau protein aggregates. Prodromal to cognitive decline, there is a selective loss of cortical excitatory synapses and neurons required for learning and memory. Zhao et al. reported that human AD brains (n=15 human subjects versus controls) and the APPswe AD-mouse model are characterized by a loss of PAK1 and PAK3 levels and activity, redistribution of phospho-PAKs and changes in cofilin and drebrin content [32]. Moreover, activation of PAK1 in primary neurons can protect against Aβ oligomer-mediated dredrin loss. In 2008, the same authors reported that cytosolic PAK1 loss occurs because of aberrant PAK activation and translocation to the membrane-cytoskeletal fractions in AD brains (n=5 human subjects versus controls), in APPswe (Tg2576) AD mouse models and primary neuronal cultures treated with Aβ oligomers [81]. PAK1 translocation was followed by the rapid loss of F-actin and the spine-marker PDS95, resembling postsynaptic and dendritic spine defects that occurs in AD [81]. Therefore, the authors concluded that aberrant PAK activation and translocation to the membrane may sequester cytosolic PAK causing, in turn, defects in spine dynamics and cognitive impairments [82]. Additional studies support the notion that alteration in PAK activity is involved in AD pathogenesis. In the APP695 (PDAPP) AD mice, it has been observed that PAK1-2-3 activation is enhanced in the hippocampus of 3-month old mice, whereas there is a clear decline at 13months, suggesting a biphasic behavior. Similarly, enhanced protein levels of PAK1-3 have been observed in early AD while a reduction of both total and cytoplasmic phospho-PAK is reported in moderate to severe human AD hippocampi (n=8 per group) [83]. In contrast, an increase in phosphorylated PAK1-3 was observed in the brain of Appswe/PSEN1dE9 mice [84], pointing to inhibition of PAK activity as a possible therapeutic approach in AD. However, several studies highlighted that ablation as well as inhibition of PAK kinase activity induces cofilin pathology and behavioral deficits in mice resembling an AD phenotype [55], [56], [32]. Specifically, a loss of total PAK has been detected in cortical samples from AD brains (n=12 human subjects per group) and downregulation of PAK correlates with the disease severity in humans [84]. Moreover, dominant-negative PAK (dnPAK) mice show spine defects and memory impairments, and PAK inactivation in 3xTg-AD mouse model aggravate AD phenotypes, suggesting that PAK activation, rather than inhibition, may be protective in AD [85] [86]. Overall, additional studies taking into account the kinetics of the neurodegenerative process rather than the endpoint will contribute to clarify the therapeutic potential of PAKs in AD.