Use of iPSCs models in studies of neurodegeneration has the potential to revolutionize our understanding of disease mechanisms. However, wide-scale adoption of iPSCs by the community has been hindered by availability of high-quality lines harboring disease-associated mutations, easy and reliable methods to differentiate these into CNS cells, and questions regarding whether they accurately model relevant disease biology. Here, we will demonstrate recent success in addressing each of these major issues. We are leading a large-scale multi-center project, the iPSC Neurodegenerative Disease Initiative (iNDI), that will a series of hundreds of isogenic mutation-harboring iPSC lines spanning 72 ADRD genes on the background of a single parental iPSC line. We will then describe recent success in generating a portfolio of transcription factor (TF)-based differentiation methods to easily and rapidly produce different neuronal subtypes, muscle, astrocytes, and microglia, and ongoing efforts to co-culture TF-differentiated cells in 3D assembloids. Finally, we will share new data from forward genomic CRISPRi synthetic lethality screens of FTD/ALS gene functions in iPSC-derived neurons, demonstrating that such screens uncover both known and new functions of these genes.
