Highlights d A CRISPR interference platform for genetic screens in human iPSC-derived neurons d Survival screens uncover genes essential for neurons, but not iPSCs or cancer cells d Single-cell RNA-seq screens reveal distinct neuronal roles for ubiquitous genes d Arrayed high-content screens uncover genes controlling neuronal morphology

No abstract

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 genomewide 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.

The asymmetric α-addition of relatively nonpolar hydrocarbon substrates, such as allyl and aryl groups, to aldehydes and ketones remains a largely unsolved problem in organic synthesis, despite the wide potential utility of direct routes to such products. We reasoned that well-established chiral amine catalysis, which activates aldehydes toward electrophile addition by enamine formation, could be expanded to this important reaction class by applying a single-electron oxidant to create a transient radical species from the enamine. We demonstrated the concept of singly occupied molecular orbital (SOMO) activation with a highly selective α-allylation of aldehydes, and we here present preliminary results for enantioselective heteroarylations and cyclization/halogenation cascades.