reduced neuronal outgrowth, and decreased neuronal firing (SMA3 > SMA2 > SMA1), and regardless of diagnosis, non-motor neurons do not die. Lee conducted three high-throughput screens for compounds to prevent cell death in SMA (ES-derived motor neurons from SMN-deficient mice, SMA patient fibroblasts, and SMA hiPSC-derived motor neurons). Unbiased screens in mouse motor neurons, human motor neurons, and human fibroblasts identified many compounds that increased SMN levels, only some of which overlapped between platforms: while some compounds that block SMN degradation were hits in all three screens, proteasome inhibitors were found in the fibroblast screen but proved toxic to motor neurons (MNs). On the basis of high content imaging data generated through the various screens, his group also observed that at the level of single cells, whether from control or SMA hiPSCs, there is cell-to-cell variation in SMN levels; individual cells with high SMN are the fittest and survive better than neighboring cells with lower SMN, implying that SMN is a general regulator of motor neuron survival, likely owing to reducing activation of the endoplasmic reticulum (ER) stress response. Moreover, inhibitors of the degradation process do not promote survival of SMN neurons below a defined basal level but shift the
