Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration.
Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
New York City, US · Author affiliation
The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. Electronic address: sauratn@mskcc.org.Location evidence
Boston, US · Author affiliation
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA; Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.Location evidence
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Original abstract
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.