In a panel of iPSC-derived dopamine neurons from PD patients with mutations in either LRRK2 or PINK1, the kinase inhibitor GW5074 was reported to protect cultures from the toxicity of valinomycin (a potassium ionophore that induces oxidative stress and thus may mimic
environmental stressors in vivo [Cooper et al., 2012]). In AD patient iPSC-derived cortical neurons that harbor duplication of the APP locus, β-secretase but not γ-secretase inhibitors were found to suppress an altered TAU phosphorylation phenotype ( Israel et al., 2012). A histone acetyltransferase inhibitor, anacardic acid, was reported to be protective in the context of TDP-43 mutant iPSC-derived motor neurons treated with the neurotoxin arsenite ( Egawa et al., 2012); anacardic acid was chosen on the basis of its potential to modify gene expression changes observed in the mutant cells.
It will be important to further validate BAY 73-4506 in vitro these candidates therapeutics in multiple independent cell cultures. Phenotypic analyses of functional neuronal parameters—such as membrane excitability or synaptic connectivity—have thus far been limited, in ZD1839 mw the context of reprogramming-based models of neurodegeneration. Recent studies using iPSC-derived neurons in the context of psychiatric disorders, such as schizophrenia (Brennand et al., 2011) and Timothy syndrome (Paşca et al., 2011 and Yazawa and Dolmetsch, 2013), have considered such functional neuronal parameters, and attempted to use these analyses in the pursuit of therapeutics.
In iPSC-derived cortical neuron cultures from schizophrenia patients and unaffected controls, synaptic connectivity was evaluated in terms of the trans-synaptic spread of a modified, fluorescently tagged rabies virus ( Brennand et al., 2011). Such synaptic connectivity appeared reduced in the schizophrenia patient iPSC-derived neurons, relative to iPSC-derived neurons from unaffected individuals. Further studies are needed to determine whether this observation can be generalized to independent patient cohorts with schizophrenia, and with respect to its utility in screening potential drugs ( Brennand et al., 2011). The different reprogramming-based neuronal models discussed above may have unique Thiamine-diphosphate kinase virtues or limitations in the context of drug screens. iPSC-based models allow for extensive expansion of cells, and thus may be beneficial in a broad high-content screen. A method developed to further facilitate the use of iPSC in high-content drug screens enables the expansion and maintenance of iPSC-derived neural progenitors (Koch et al., 2009 and Li et al., 2011; Reinhardt et al., 2013). In contrast to iPSC technology, high-content screening with direct reprogramming-based models requires expansion of the source fibroblast cultures, which is limited by senescence. The use of iNSC technology, as detailed above, may combine the advantages of these two approaches.