title: Genetic validation of a therapeutic target in a mouse model of ALS.
abstract: Neurons produced from stem cells have emerged as a tool to identify new therapeutic targets for neurological diseases such as amyotrophic lateral sclerosis (ALS). However, it remains unclear to what extent these new mechanistic insights will translate to animal models, an important step in the validation of new targets. Previously, we found that glia from mice carrying the SOD1G93A mutation, a model of ALS, were toxic to stem cell-derived human motor neurons. We use pharmacological and genetic approaches to demonstrate that the prostanoid receptor DP1 mediates this glial toxicity. Furthermore, we validate the importance of this mechanism for neural degeneration in vivo. Genetic ablation of DP1 in SOD1G93A mice extended life span, decreased microglial activation, and reduced motor neuron loss. Our findings suggest that blocking DP1 may be a therapeutic strategy in ALS and demonstrate that discoveries from stem cell models of disease can be corroborated in vivo.
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Stanley Center for Psychiatric Research, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: A Sophie
authors.initials: AS
authors.lastname: de Boer
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Stanley Center for Psychiatric Research, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Koszka
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Stanley Center for Psychiatric Research, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Kiskinis
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Stanley Center for Psychiatric Research, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Stanley Center for Psychiatric Research, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Davis-Dusenbery
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Stanley Center for Psychiatric Research, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. eggan@mcb.harvard.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000628:therapy*; D000818:Animals; D018920:Coculture Techniques; D019610:Cytoprotection; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008136:Longevity; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000473:pathology; D011982:Receptors, Prostaglandin / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D011982:Receptors, Prostaglandin; C527097:prostanoid D receptor 1, mouse