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Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity

Wertz, Mary H. and Mitchem, Mollie R. and Pineda, S. Sebastian and Hachigian, Lea J. and Lee, Hyeseung and Lau, Vanessa and Powers, Alex and Kulicke, Ruth and Madan, Gurrein K. and Colic, Medina and Therrien, Martine and Vernon, Amanda and Beja-Glasser, Victoria F. and Hegde, Mudra and Gao, Fan and Kellis, Manolis and Hart, Traver and Doench, John G. and Heiman, Myriam (2020) Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity. Neuron, 106 (1). pp. 76-89. ISSN 0896-6273. PMCID PMC7181458. doi:10.1016/j.neuron.2020.01.004.

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Unbiased in vivo genome-wide genetic screening is a powerful approach to elucidate new molecular mechanisms, but such screening has not been possible to perform in the mammalian central nervous system (CNS). Here, we report the results of the first genome-wide genetic screens in the CNS using both short hairpin RNA (shRNA) and CRISPR libraries. Our screens identify many classes of CNS neuronal essential genes and demonstrate that CNS neurons are particularly sensitive not only to perturbations to synaptic processes but also autophagy, proteostasis, mRNA processing, and mitochondrial function. These results reveal a molecular logic for the common implication of these pathways across multiple neurodegenerative diseases. To further identify disease-relevant genetic modifiers, we applied our screening approach to two mouse models of Huntington’s disease (HD). Top mutant huntingtin toxicity modifier genes included several Nme genes and several genes involved in methylation-dependent chromatin silencing and dopamine signaling, results that reveal new HD therapeutic target pathways.

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Additional Information:© 2020 Elsevier Inc. Received 22 July 2019, Revised 3 December 2019, Accepted 6 January 2020, Available online 30 January 2020. The authors thank the CHDI Foundation for providing the zQ175 mice used in this study. This work was supported by NIH/NINDS award R01 NS085880 (M. Heiman); an award from the JPB Foundation (M. Heiman); an award from the Bev Hartig Huntington’s Disease Foundation (M. Heiman); a Fay/Frank Seed Award from the Brain Research Foundation (M. Heiman); the Jeptha H. and Emily V. Wade Award (M. Heiman); fellowships from the JPB Foundation and the Hereditary Disease Foundation (M.H.W.); the NIH (5T32EB019940-05; S.S.P.); and the JPB Foundation (H.L.). T.H. and M.C. were supported by NIH/NIGMS award R35GM130119 (T.H.), CPRIT grant RR160032 (T.H.), and the NIH/NCI Cancer Center Support Grant P30 CA016672. Author Contributions: M.H.W. performed the in vivo screening and Nme1 experiments and analyses. M.R.M., A.P., and L.J.H. performed the intracranial stereotaxic injections. M.C. and T.H. performed the DrugZ analysis. R.K. conducted immunohistochemical experiments and mouse handling. A.V. assisted in mouse handling. H.L., G.K.M., and V.F.B.-G. assisted in Nme1 experiments. M.T. assisted in Nme1 experiments and data analysis. S.S.P. and H.L. prepared and S.S.P. analyzed the snRNA-seq data of Nme1OX experiments. L.J.H. collected and F.G. analyzed the RNA-seq data. M. Hegde and J.G.D. assisted in screening design and data analysis. M.H.W. and M. Heiman wrote the manuscript. M. Heiman conceived and supervised the project. All authors reviewed and approved the final manuscript. The authors declare no competing interests.
Funding AgencyGrant Number
NIHR01 NS085880
Bev Hartig Huntington’s Disease FoundationUNSPECIFIED
Brain Research FoundationUNSPECIFIED
Jeptha H. and Emily V. Wade AwardUNSPECIFIED
Hereditary Disease FoundationUNSPECIFIED
Cancer Prevention and Research Institute of TexasRR160032
NIHP30 CA016672
Subject Keywords:Huntington’s disease; genome-wide screening; neuronal essential genes; Nme1
Issue or Number:1
PubMed Central ID:PMC7181458
Record Number:CaltechAUTHORS:20200130-124820336
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Official Citation:Mary H. Wertz, Mollie R. Mitchem, S. Sebastian Pineda, Lea J. Hachigian, Hyeseung Lee, Vanessa Lau, Alex Powers, Ruth Kulicke, Gurrein K. Madan, Medina Colic, Martine Therrien, Amanda Vernon, Victoria F. Beja-Glasser, Mudra Hegde, Fan Gao, Manolis Kellis, Traver Hart, John G. Doench, Myriam Heiman, Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity, Neuron, Volume 106, Issue 1, 2020, Pages 76-89.e8, ISSN 0896-6273,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101005
Deposited By: Tony Diaz
Deposited On:30 Jan 2020 21:34
Last Modified:09 Feb 2022 20:47

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