Neurons derived from induced pluripotent stem cells(iPSCs)are increasingly employed to model human neurological diseases.However,these neurons are reset to an embryonic stage during the reprogramming process and thus inappropriate to model adult-onset neurodegeneration.In contrast,direct reprogrammed neurons without going through a stem cell stage maintain ageassociated features of their origin.By combining small molecules and transcription factors for direct reprogramming,we have established a very robust and efficient approach to produce spinal motor neurons from adult human fibroblasts.The neurons converted from healthy humans maintain ageassociated features and become functionally mature by firing repetitive action potentials and forming neuromuscular junctions in co-culture.In contrasts,motor neurons converted from fibroblasts of adult human patients with amyotrophic lateral sclerosis(ALS)show degenerative features,such as poor survival and inability to control muscle contraction.A candidate approach revealed that the small molecule kenpaullone can rescue most of these disease phenotypes.To identify additional small molecules for therapeutic development,we further conducted an unbiased screen of nearly two thousand compounds.The screening process and positive hits will be discussed during the meeting.