However, it will be critical to

keep in mind that iPS cells will be most powerfully leveraged as tools for biomedical research when they are used alongside existing animal, cell, and molecular models of neural degeneration. If disease-specific iPS cells are to be translated into clinically JQ1 mouse informative models for mechanistic studies and therapeutic drug discovery, several basic requirements must ideally be met. First, it will be important to optimize methods for differentiating stem cells into the particular neural cell type of interest. In the specific case of the spinal motor neurons affected in ALS and SMA and midbrain dopaminergic neurons in PD, methods described in mouse and human embryonic stem cells have translated fairly well into iPS cells, though they are far from perfect. It may further be necessary to identify culture conditions to produce specific subclasses of the desired cell type. For example, in ALS, selective subclasses of motor neurons degenerate whereas other subclasses are preferentially spared (for example motor neurons of the

oculomotor complex in the midbrain controlling eye movements and motor neurons of sacral spinal cord controlling bowel and bladder function). In PD, the A9 nigrostrial dopaminergic selleckchem projection neurons are preferentially affected and are paramount for the motor symptoms that typify this disorder. Second, phenotypic assays relevant to the disease process need to be established and advances in genetic modifications to create isogenic control lines will impart rigorous methods to compare disease versus control phenotypes. Needless to say, iPS cell models alone will not be able to produce clinically important read-outs of memory dysfunction and behavioral changes in AD or frontotemporal dementia, tremor, bradykinesia, and rigidity in PD, or reduced forced vital capacity, swallowing dysfunction,

dysarthria, or limb motor impairment in ALS. However, recapitulation of key molecular, cellular, and anatomical changes involved in disease are well within the scope of disease-related phenotypes in culture. Expected phenotypes based on previously established animal and cellular models and observations from neuropathological studies should serve as a means to establish hypotheses or help validate the specific iPS L-NAME HCl model but the identification of novel mechanisms or cellular phenotypes remains an exciting possibility. Importantly, iPS cell models will allow for the study of human pathophysiology and pharmacologic responses. Lastly, iPS cell-based models may provide a new opportunity to understand selective vulnerability of populations of neurons to discrete degenerative stimuli, a theme common to many neurological disorders. Thus, in coming closer to creating more relevant cellular models of human neurological disease, perhaps what we can create, we can understand. S.