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

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

doi:10.1016/j.neuron.2020.01.004

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

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

Bioinformatics & Computational Biology

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	76-89.e8
Journal	Neuron
Volume	106
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2020.01.004
State	Published - Apr 8 2020

Keywords

Huntington's disease
Nme1
genome-wide screening
neuronal essential genes

ASJC Scopus subject areas

General Neuroscience

MD Anderson CCSG core facilities

Bioinformatics Shared Resource

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10.1016/j.neuron.2020.01.004

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Wertz, M. H., Mitchem, M. R., Pineda, S. S., Hachigian, L. J., Lee, H., Lau, V., Powers, A., Kulicke, R., Madan, G. K., Colic, M., Therrien, M., Vernon, A., Beja-Glasser, V. F., Hegde, M., Gao, F., Kellis, M., Hart, T., Doench, J. G., & Heiman, M. (2020). Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity. Neuron, 106(1), 76-89.e8. https://doi.org/10.1016/j.neuron.2020.01.004

Wertz, MH, Mitchem, MR, Pineda, SS, Hachigian, LJ, Lee, H, Lau, V, Powers, A, Kulicke, R, Madan, GK, Colic, M, Therrien, M, Vernon, A, Beja-Glasser, VF, Hegde, M, Gao, F, Kellis, M, Hart, T, Doench, JG & Heiman, M 2020, 'Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity', Neuron, vol. 106, no. 1, pp. 76-89.e8. https://doi.org/10.1016/j.neuron.2020.01.004

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abstract = "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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AU - Therrien, Martine

AU - Vernon, Amanda

AU - Beja-Glasser, Victoria F.

AU - Hegde, Mudra

AU - Gao, Fan

AU - Kellis, Manolis

AU - Hart, Traver

AU - Doench, John G.

AU - Heiman, Myriam

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

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