. Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat Commun. 2015 Jun 10;6:7319. PubMed.


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  1. I think this is a spectacular paper. The researchers are the first to provide any functional evidence on how UNC13a might be involved in motor neuron death. This is important considering UNC13a confers risk for developing ALS, but there two studies suggesting that the gene negatively influences survival in ALS in a profound way (6 to 12 months shorter lifespan).

    Understanding the mechanisms underpinning the role of UNC13a in ALS, therefore, seems a logical step for identifying potential therapeutic targets. Indeed, it seems Vérièpe and colleagues have not only found that the innate immune system is involved, but have unraveled a considerable part of the pathways involved. Undoubtedly, this paper will help identify further treatment strategies for ALS.  

    View all comments by Michael van Es
  2. The article by Vérièpe et al. provides elegant evidence supporting the involvement of innate immunity and cell-non-autonomous pathways in ALS. Expression of TDP-43 and FUS in C. elegans motor neurons led to motility defects and motor neuron degeneration by activating an innate immune response pathway. Although innate immune microglia and an adaptive immune system are lacking in C. elegans, several specific steps leading to neurodegeneration parallel pathways of disease activation in mammalian ALS. The most cogent finding is that UNC-13-mediated secretion of signals from motor neurons was required for induction of the immune response and degeneration of motor neurons.

    The UNC-13-mediated secretions activated the TIR-1 pathway and innate response genes in the distal intestinal and hypodermal cells, just as secreted molecules activate glial TLR-4 and NF-κB innate response genes in microglia in mammalian ALS. UNC-13-mediated secretions from motor neurons also led to neuronal TIR-1 activation initiating the neurodegenerative cascade. The molecular composition of the secreted factors as well as their specific receptors remains to be identified. Nevertheless, the key involvement of UNC-13 supports the importance of cell-non-autonomous pathways in TDP-43 and FUS-mediated neurodegeneration in C. elegans, and by analogy in human ALS, especially since the human orthologue, UNC13A, has been reported to modify disease progression and duration in ALS. Such studies also support the importance of the immune system in motor neuron degeneration.

    Identifying and neutralizing these secretions offers a potential therapeutic approach to preventing pro-inflammatory immune activation and the resulting neurodegenerative cascade in ALS.

    View all comments by Stanley H. Appel

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