CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neuronal cell death.

Autor: Pavlou S; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK. sof_pav@hotmail.com.; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. sof_pav@hotmail.com., Foskolou S; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK.; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Patikas N; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK., Field SF; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK.; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Papachristou EK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK., Santos C; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK., Edwards AR; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK., Kishore K; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK., Ansari R; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK., Rajan SS; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK.; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Fernandes HJR; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK.; Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK., Metzakopian E; UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK. em698@medschl.cam.ac.uk.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Mar 09; Vol. 13 (1), pp. 3934. Date of Electronic Publication: 2023 Mar 09.
DOI: 10.1038/s41598-023-31141-6
Abstrakt: Accumulation of aggregated and misfolded proteins, leading to endoplasmic reticulum stress and activation of the unfolded protein response, is a hallmark of several neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Genetic screens are powerful tools that are proving invaluable in identifying novel modulators of disease associated processes. Here, we performed a loss-of-function genetic screen using a human druggable genome library, followed by an arrayed-screen validation, in human iPSC-derived cortical neurons. We identified and genetically validated 13 genes, whose knockout was neuroprotective against Tunicamycin, a glycoprotein synthesis inhibitor widely used to induce endoplasmic reticulum stress. We also demonstrated that pharmacological inhibition of KAT2B, a lysine acetyltransferase identified by our genetic screens, by L-Moses, attenuates Tunicamycin-mediated neuronal cell death and activation of CHOP, a key pro-apoptotic member of the unfolded protein response in both cortical and dopaminergic neurons. Follow-up transcriptional analysis suggested that L-Moses provided neuroprotection by partly reversing the transcriptional changes caused by Tunicamycin. Finally, L-Moses treatment attenuated total protein levels affected by Tunicamycin, without affecting their acetylation profile. In summary, using an unbiased approach, we identified KAT2B and its inhibitor, L-Moses, as potential therapeutic targets for neurodegenerative diseases.
(© 2023. The Author(s).)
Databáze: MEDLINE
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