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Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity.
Wertz, Mary H; Mitchem, Mollie R; Pineda, S Sebastian; Hachigian, Lea J; Lee, Hyeseung; Lau, Vanessa; Powers, Alex; Kulicke, Ruth; Madan, Gurrein K; Colic, Medina; Therrien, Martine; Vernon, Amanda; Beja-Glasser, Victoria F; Hegde, Mudra; Gao, Fan; Kellis, Manolis; Hart, Traver; Doench, John G; Heiman, Myriam.
Afiliação
  • Wertz MH; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Mitchem MR; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Pineda SS; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.
  • Hachigian LJ; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Lee H; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Lau V; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Powers A; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kulicke R; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Madan GK; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.
  • Colic M; University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Therrien M; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Vernon A; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Beja-Glasser VF; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research at MIT, Cambridge, MA 02139, USA.
  • Hegde M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Gao F; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Bioinformatics Resource Center in the Beckman Institute at Caltech, Pasadena, CA 91125, USA.
  • Kellis M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA 02139, USA.
  • Hart T; University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Heiman M; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mheiman@mit.edu.
Neuron ; 106(1): 76-89.e8, 2020 04 08.
Article em En | MEDLINE | ID: mdl-32004439
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sobrevivência Celular / Neostriado / Doença de Huntington / Proteína Huntingtina / Neurônios Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sobrevivência Celular / Neostriado / Doença de Huntington / Proteína Huntingtina / Neurônios Idioma: En Ano de publicação: 2020 Tipo de documento: Article