Science Translational Medicine 2014-08-06

Genetic validation of a therapeutic target in a mouse model of ALS.

A Sophie de Boer, Kathryn Koszka, Evangelos Kiskinis, Naoki Suzuki, Brandi N Davis-Dusenbery, Kevin Eggan

Index: Sci. Transl. Med. 6(248) , 248ra104, (2014)

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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. Copyright © 2014, American Association for the Advancement of Science.