The lack of the formation of pathological aggregates in dopaminergic cells from sporadic PD-iPS cells gives some pause as to whether patient-derived iPS cells from a sporadic or late-onset disorder will

show relevant phenotypes spontaneously in the time frame of in vitro experiments or in vivo assays. It is often argued that the time to produce disease in a patient correlates to the predicted length it may take to recapitulate disease phenotypes in culture. There is probably some truth to this assumption, as evidenced by the reported successes in iPS cell disease modeling in pediatric genetic diseases summarized previously. Development of methods to accurately correlate how a stem cell-derived buy INK 128 neuron in culture correlates ontologically with the in vivo equivalent could be useful. However, neuronal dysfunction

and degeneration as a result of the neurodegenerative process probably occurs much earlier than the initial neurological manifestations that characterize disease. For example, prior to the onset of the motor component of PD, a significant number of dopaminergic neurons have already been lost. Moreover, nonmotor manifestations can selleck inhibitor predate motor manifestations by years. In PD, one of the earliest symptoms of disease may be olfactory and autonomic dysfunction and initial α-synuclein-positive Lewy body pathology may occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus (Braak et al., 2003). It would thus seem reasonable, in GPX6 addition to studying midbrain dopaminergic neurons, whose degeneration causes the motor component of PD, to also consider developing directed differentiation methods from PD-iPS cells to obtain the cell types affected earliest in the disease. Methods to accelerate the time to pathology in vitro

will probably be important in adult-onset disease. Cellular stressors such as oxidative stress, growth factor withdrawal, starvation, selective neurotoxins, and heat shock may help reveal differences in iPS cell models. Taking this approach, dopaminergic neurons from iPS cell lines of an early-onset PD patient with a known mutation in LRRK2, demonstrated increased proportions of caspase-3 activation suggesting a selective vulnerability when exposed to a variety of cellular stressors including hydrogen peroxide, proteosome inhibition, and 6-OHDA exposure, though the differences were modest ( Nguyen et al., 2011). Differentiated neuronal cultures from PD-iPS cells expressed higher levels of α-synuclein, as compared to the neurons from control iPS and H9 ES cells, but whether this translated to pathological cytoplasmic aggregates was not discussed. Given that these results were based on lines generated from one patient and one healthy control, further work on additional patient and control lines is warranted. Regardless of these limitations, similar strategies are likely to be informative in iPS cell models of ALS, AD, and HD ( Zhang et al., 2010).