Project Summary Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing public health challenges, for which effective treatment is still lacking. At least two major themes that have emerged from the studies of ALS/FTD, concerning etiology related to both RNA metabolism and protein homeostasis. However, the mechanisms of RNA and protein homeostasis are not completely independent. UBQLN2 is a protein quality control factor that has been linked to ALS/FTD. Mutations in UBQLN2 have been linked to ALS/FTD, and UBQLN2 immunoreactivity is found in ALS/FTD and other neurodegenerative conditions. We have identified a role for UBQLN2 in antagonizing the aberrant phase transition and stress granule formation of mutant FUS, behaviors that potentially disrupt the RNA- processing functions of FUS and lead to neurodegeneration. The induced pluripotent stem cells (iPSC)-derived models have become instrumental experimental systems for study the pathological mechanisms and therapeutic interventions for neurodegenerative diseases including Alzheimer’s disease and related dementias (ADRD). Here we will characterize iPSC lines that harbor ADRD-related mutations in order to develop better ADRD disease models. The project is aimed at deep quality control and molecular phenotyping of the iPSC lines to generate predictable and reliable models. The outcome of the studies will not only provide clinically relevant models for this form of neurodegeneration diseases such as ALS/FTD but also generate insights into the pathogenic mechanisms as well as therapeutic applications for the devasting diseases.