The number of individuals over 60 years of age in the US is projected to increase nearly 3 fold by 2050. This shift has the potential to wreak havoc on the health care system with sky rocketing costs of Medicare. Neurodegenerative diseases, whose number one risk factor is age, have the potential to lead the way as few successful therapies exist for disease like Alzheimer's, Parkinson's, ALS, and FTLD. For this reason, it is essential that basic researchers uncover the underlying mechanisms of disease in order to provide new therapeutic avenues to prevent, slow down, or cure these diseases. I have been studying the protein - TDP-43 - which has recently been implicated in sporadic ALS and FTLD-U, together called TDP-43 proteinopathies. Using yeast as a model system of TDP-43 toxicity, I have screened 200,000 compounds that ameliorate this toxicity and provide promise as probes to understand how TDP-43 causes cell death, as well as being lead compounds for future therapeutic development. In this fellowship, I will generate a mouse embryonic stem cell-derived model in which mESCs express wild-type or mutant TDP-43. These cells will be differentiated into motor and cortical neurons. After characterization, I will test compound efficacy in this model to identify those that have conserved molecular targets and pathways. Finally, I will identify the targets or targeted pathways of these compounds by using the power of yeast genetics to screen for genetic interactions. This last approach has been highly successful in identifying pathways and proteins affected by a number of compounds. These experiments will help delineate disease mechanisms of TDP-43 proteinopathies and provide lead compounds that can be subsequently studied for therapeutic potential. Sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) are two neurodegenerative diseases characterized by the deposition of a protein called TDP-43. I have screened over 200,000 compounds for those that rescue a model of TDP-43 toxicity. I will study lead compounds in a mouse embryonic stem cell-derived neuronal model to help elucidate the mechanism of these two catastrophic disorders and provide lead compounds for further development.