ALS is a progressive neurodegenerative disease that primarily affects motor neurons (MNs). It results in paralysis and loss of control of vital functions, such as breathing, leading to premature death. Much scientific evidence indicates that ALS is due to the buildup of toxic misfolded proteins in key neuronal populations that leads to neurodegeneration. In this CIRM-funded project, we are developing drugs that can improve a cellular process called “autophagy” by which cells, including neurons, clear out built-up toxic misfolded proteins and increase their longevity. We had discovered that a series of FDA-approved drugs already on the market for other indications happen to induce autophagy in a manner that is independent of their original purpose. Our goal is to show that these FDA-approved drugs can induce autophagy and slow neurodegeneration in ALS patient-derived neurons, and to repurpose these drugs for ALS. In the last year, we have made significant progress towards testing these drugs on neurons that we derived from induced pluripotent stem cells engineered from skin cells taken from ALS patients. We have built robotic microscopes that can rapidly image ALS patient neurons that are treated with drugs in the lab and determine whether any of these “autophagy-inducing” FDA-approved drugs slowdown the rate of neurodegeneration. We have optimized large-scale methods to grow patient neurons, treat them with drugs, image them over many days, and analyze the images to measure neurodegeneration. In August 2014, we published a paper in the journal Nature Chemical Biology that showed two FDA-approved drugs can in fact induce autophagy and increase the clearing of an ALS-related protein called TDP43 in neurons. The drugs were also able to slow neurodegeneration in neurons and astrocytes derived from a familial ALS patient with an altered version of the TDP43 gene. We have now obtained stem cells from broader types of familial ALS as well as sporadic ALS patients, have made neurons from their stem cells, and have treated their stem cell-derived neurons with more than 10 autophagy-inducing drugs at varying concentrations to determine whether autophagy-inducers can slow neurodegeneration in neurons from broader forms of ALS. These neurons are currently being imaged using our robotic microscope. In addition, we have started to make astrocytes from patient stem cells and plan to test the drugs on astrocytes in the coming months.