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

Sci Transl Med
Authors
Keywords
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.

Year of Publication
2014
Journal
Sci Transl Med
Volume
6
Issue
248
Pages
248ra104
Date Published
2014 Aug 06
ISSN
1946-6242
URL
DOI
10.1126/scitranslmed.3009351
PubMed ID
25100738
Links
Grant list
Howard Hughes Medical Institute / United States