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

  • Cell Stem Cell. 2024 Jun 21:S1934-5909(24)00210-8. doi: 10.1016/j.stem.2024.06.001.
Nathalie Saurat  1 ,  Andrew P Minotti  2 ,  Maliha T Rahman  3 ,  Trisha Sikder  4 ,  Chao Zhang  5 ,  Daniela Cornacchia  4 ,  Johannes Jungverdorben  6 ,  Gabriele Ciceri  4 ,  Doron Betel  7 ,  Lorenz Studer  8
Affiliations
  • 1. 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: [email protected].
  • 2. 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; Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
  • 3. 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; Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • 4. 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.
  • 5. 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.
  • 6. 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.
  • 7. 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.
  • 8. 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: [email protected].
PMID: 38917806 DOI: 10.1016/j.stem.2024.06.001
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.

Keywords
Alzheimer’s disease; Parkinson’s disease; aging; cortical neurons; disease modeling; dopamine neurons; human pluripotent stem cells; neddylation; proteostasis; senescence.
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