Neuron-supporting glial cells can rebel in amyotrophic lateral sclerosis, turning against the very motor neurons they are supposed to nurse. Blocking the microglial prostanoid receptor DP1 alleviates this toxicity, according to a paper in the August 6 Science Translational Medicine. Researchers in the laboratory of Kevin Eggan at Harvard University in Cambridge, Massachusetts, got the strategy to work in neurons derived from stem cells, then confirmed it in a mouse model of ALS. “Our results firmly establish inhibition of the DP1 receptor as a therapeutic target for ALS," the authors wrote.

Researchers have long suspected that the death knell for motor neurons in ALS sounds not from within but from glia, which secrete some unknown toxic factor (see Apr 2007 news story). In a previous study, the Eggan group showed that glia from ALS-model mice make more of the pro-inflammatory prostaglandin D2, and that microglia treated with this lipid hormone damaged neurons (see Dec 2008 news story). In the current work, first author Sophie de Boer of Leiden University Medical Center, Netherlands, and colleagues studied the prostaglandin D2 receptor DP1. The researchers used small molecules that either trigger or block the receptor, which they applied to co-cultures of motor neurons and glia. They derived the neurons from human embryonic stem cells, and the glia, comprising both astrocytes and microglia, from nontransgenic mice or ALS-model animals expressing mutant human superoxide dismutase 1.

Normally, the mSOD1 mouse glia kill about one-third of the human motor neurons after 10 days of co-culture. However, when de Boer pre-treated the glial cells with the DP1 blocker BW A868C, it protected the neurons (see image below). In contrast, wild-type mouse glia, which normally leave human neurons unharmed, destroyed them when treated with the DP1 activator BW 245C. 

Mutant SOD1 glia (left) normally slaughter motor neurons (labeled with green fluorescent protein). Treating the cultures with a DP1 blocker (right) preserves the neurons. [Image courtesy of Science Translational Medicine/AAAS.]

Mutant SOD1 glia missing DP1 were less toxic in co-cultures, confirming that they need prostaglandin D2 signaling to turn them into motor neuron killers. To see if the microglia or the astrocytes were the killers in the mixed cultures, de Boer and colleagues repeated the experiment with purified cultures of each glial type, from either mouse or human. Again, turning on glial DP1 dispatched the neurons. Purified astrocytes were not toxic to motor neurons.

How do mutant SOD1 and DP1 signaling relate? The authors added the mutant SOD1 gene to human glia and saw an increase in DP1. Séverine Boillée of University Pierre and Marie Curie in Paris, and Carol Marchetto of the Salk Institute in La Jolla, California, told Alzforum it would be interesting to investigate if other ALS mutations also modulated DP1 expression.  

To extend their findings to an in vivo model, de Boer and colleagues monitored disease progression in the mSOD1 animals. Normally, mSOD1 mice sicken around 15 weeks of age. Animals lacking DP1 became ill around the same time, but lived for about 10 days longer than the typical 19-week lifespan. Necropsies confirmed that more spinal motor neurons survived in DP1-negative animals than mSOD1 controls.

Boillée noted that the paper leaves open several questions, not least how DP1 signaling renders microglia toxic. Perhaps there is an inflammatory reaction that leads the glia to attack neurons, Marchetto speculated. That the DP1 antagonist works on both mouse and human microglia is “promising” for a future therapy, commented Boillée. The authors write, “Although the chemical compounds used in the assays we report here are not currently in therapeutic development … highly potent and selective DP1 antagonists suitable for clinical study have been developed that could be repurposed for ALS” (Li et al., 2010).—Amber Dance


  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.

    View all comments by Severine Boillee

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News Citations

  1. Glia—Absolving Neurons of Motor Neuron Disease
  2. ALS in a Dish? Studying Motor Neurons from Human Stem Cells

Paper Citations

  1. . Potent and highly selective DP1 antagonists with 2,3,4,9-tetrahydro-1H-carbazole as pharmacophore. Bioorg Med Chem Lett. 2010 Dec 15;20(24):7462-5. Epub 2010 Oct 12 PubMed.

Further Reading


  1. . 15-Deoxy-Delta(12,14)-prostaglandin J(2): the endogenous electrophile that induces neuronal apoptosis. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7367-72. PubMed.
  2. . A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2003 Apr;17(6):725-7. PubMed.
  3. . Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. 2004 Feb;88(3):576-82. PubMed.
  4. . Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol. 2006 Jul;60(1):22-31. PubMed.
  5. . Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann Neurol. 2001 Feb;49(2):176-85. PubMed.
  6. . Inhibition of cyclooxygenase-2 protects motor neurons in an organotypic model of amyotrophic lateral sclerosis. Ann Neurol. 2000 Nov;48(5):792-5. PubMed.

Primary Papers

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