%0 Journal Article %A Ruilin Tian %A Anthony Abarientos %A Jason Hong %A Sayed Hadi Hashemi %A Rui Yan %A Mike A. Nalls %A Andrew B. Singleton %A Ke Xu %A Faraz Faghri %A Martin Kampmann %T Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis %D 2020 %R 10.1101/2020.06.27.175679 %J bioRxiv %P 2020.06.27.175679 %X Single-cell transcriptomics provide a systematic map of gene expression in different human cell types. The next challenge is to systematically understand cell-type specific gene function. The integration of CRISPR-based functional genomics and stem cell technology enables the scalable interrogation of gene function in differentiated human cells. Here, we present the first genome-wide CRISPR interference and CRISPR activation screens in human neurons. We uncover pathways controlling neuronal response to chronic oxidative stress, which is implicated in neurodegenerative diseases. Unexpectedly, knockdown of the lysosomal protein prosaposin strongly sensitizes neurons, but not other cell types, to oxidative stress by triggering the formation of lipofuscin, a hallmark of aging, which traps iron, generating reactive oxygen species and triggering ferroptosis. We also determine transcriptomic changes in neurons following perturbation of genes linked to neurodegenerative diseases. To enable the systematic comparison of gene function across different human cell types, we establish a data commons named CRISPRbrain.Competing Interest StatementM.K. has filed a patent application related to CRISPRi and CRISPRa screening (PCT/US15/40449) and serves on the Scientific Advisory Board of Engine Biosciences and Casma Therapeutics. %U https://www.biorxiv.org/content/biorxiv/early/2020/07/22/2020.06.27.175679.full.pdf