Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Aging is the biggest risk factor for the development of Alzheimer’s disease (AD). Here, we performed a whole-genome CRISPR screen to identify regulators of neuronal age and show that the neddylation pathway regulates both cellular age and AD neurodegeneration in a human stem cell model. Specifically, we demonstrate that blocking neddylation increased cellular hallmarks of aging and led to an increase in Tau aggregation and phosphorylation in neurons carrying the APPswe/swe mutation. Aged APPswe/swe but not isogenic control neurons also showed a progressive decrease in viability. Selective neuronal loss upon neddylation inhibition was similarly observed in other isogenic AD and in Parkinson’s disease (PD) models, including PSENM146V/M146V cortical and LRRK2G2019S/G2019S midbrain dopamine neurons, respectively. This study indicates that cellular aging can reveal late-onset disease phenotypes, identifies new potential targets to modulate AD progression, and describes a strategy to program age-associated phenotypes into stem cell models of disease. [Display omitted] •CRISPR screen uncovers candidate mediators of cellular aging and neurodegeneration•Inhibiting neddylation in hPSC-derived neurons induces age-associated phenotypes•Neddylation and genetic vulnerability synergize to trigger late-onset pathologies•Strategy is applied to modeling late-onset phenotypes in hPSC models of AD and PD In this article, Saurat, Studer, and colleagues use a whole-genome CRISPR screening approach to identify neddylation as a candidate regulator of neuronal aging. Inducing neuronal aging by neddylation inhibition synergized with AD or PD genetic risk to trigger late-onset Tau and neuronal loss phenotypes in vitro.