title: Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease.
abstract: Huntington's disease, the most common inherited neurodegenerative disease, is characterized by a dramatic loss of deep-layer cortical and striatal neurons, as well as morbidity in midlife. Human genetic studies led to the identification of the causative gene, huntingtin. Recent genomic advances have also led to the identification of hundreds of potential interacting partners for huntingtin protein and many hypotheses as to the molecular mechanisms whereby mutant huntingtin leads to cellular dysfunction and death. However, the multitude of possible interacting partners and cellular pathways affected by mutant huntingtin has complicated efforts to understand the etiology of this disease, and to date no curative therapeutic exists. To address the general problem of identifying the disease-phenotype contributing genes from a large number of correlative studies, here we develop a synthetic lethal screening methodology for the mammalian central nervous system, called SLIC, for synthetic lethal in the central nervous system. Applying SLIC to the study of Huntington's disease, we identify the age-regulated glutathione peroxidase 6 (Gpx6) gene as a modulator of mutant huntingtin toxicity and show that overexpression of Gpx6 can dramatically alleviate both behavioral and molecular phenotypes associated with a mouse model of Huntington's disease. SLIC can, in principle, be used in the study of any neurodegenerative disease for which a mouse model exists, promising to reveal modulators of neurodegenerative disease in an unbiased fashion, akin to screens in simpler model organisms.
authors.affiliation: The Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and.
authors.forename: Reut
authors.initials: R
authors.lastname: Shema
authors.affiliation: The Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and.
authors.forename: Ruth
authors.initials: R
authors.lastname: Kulicke
authors.affiliation: The Broad Institute of MIT and Harvard University, Cambridge, MA 02142;
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.affiliation: The Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and.
authors.forename: Rachael
authors.initials: R
authors.lastname: Stein
authors.affiliation: The Broad Institute of MIT and Harvard University, Cambridge, MA 02142;
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: The Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 mheiman@MIT.edu.
authors.forename: Myriam
authors.initials: M
authors.lastname: Heiman
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002490:Central Nervous System / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D009043:Motor Activity; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D005979:Glutathione Peroxidase; C000597091:Gpx6 protein, mouse
keywords: Huntington’s disease; glutathione peroxidase; pooled screening; striatum; synthetic lethality