. Genetic validation of a therapeutic target in a mouse model of ALS. Sci Transl Med. 2014 Aug 6;6(248):248ra104. PubMed.


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  1. Previous work from this group has shown that mixed glial cells expressing mutant SOD1 were toxic to motor neurons, as were wild-type glial cells treated with prostaglandin D2. Here they wanted to analyze which receptor (DP1 or DP2) on glial cells was responsible for this neurotoxicity. They discovered that it was DP1.

    The authors also show that microglial cells from mice expressing human SOD1 are toxic to stem-cell derived human motor neurons. This study clearly demonstrates that there is a non-cell autonomous toxic effect of ALS microglial cells toward motor neurons, both with human stem-cell derived motor neurons using a DP1 antagonist and glial cells expressing or not DP1, and in vivo in a mice-mating experiment between SOD1G93A ALS mice and DP1-deleted mice.

    These data now open another question: Which factor is released by glial cells when they are activated through DP1? Interestingly, blocking DP1 receptors had a long-lasting effect because even after washing the cells, the toxicity was still attenuated. Using purified neurons, astrocytes, and microglial cells, the authors found that DP1 was expressed by glial cells rather than motor neurons, and that the highest level of expression was obtained from mutant SOD1-expressing microglial cells. It would be interesting to know if microglial cells expressing other ALS-linked genes also overexpress DP1 and whether simply activating microglial cells (i.e., by other than mutant ALS genes) is sufficient to lead to DP1 activation.

    Lastly, the authors reported that a DP1 antagonist works on both mouse glial cells and human cells. This receptor therefore looks promising for potential therapeutic strategies. It would be interesting to know whether this potent DP1 antagonist could be used in vivo in symptomatic mutant SOD1 ALS mice and if it slows disease progression.

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  1. Blocking Glial Receptor Protects Motor Neurons in Culture and Mice