. TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell. 2018 Sep 6;174(6):1477-1491.e19. Epub 2018 Aug 23 PubMed.


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  1. This manuscript from Xu et al. demonstrates that haploinsufficiency for TBK1, a gene known to contribute to the risk of ALS, is sufficient to lead to neurodegenerative phenotypes when on a background of mice lacking one copy of the kinase TAK1. Interestingly, these phenotypes are dependent on RIPK1 activity and are reversed in RIPK1 kinase dead mice. As aging results in a reduction of TAK1 expression in human brain, this work provides additional support for the idea that mutations in TBK1 contribute to disease at least in part through modulation of RIPK1 activity in the aged brain. When taken along with the data from optineurin (OPTN) null animals previously published by the same group, these results suggest that RIPK1 inhibition may provide therapeutic benefit for at least a subset of ALS patients.

    Moving forward, it will be interesting to better understand whether the decrease in TAK1 expression observed in humans during aging has the same impact on RIPK1 signaling as what is observed in TAK1-heterozygous animals. In addition, gaining an improved understanding of the factors that drive RIPK1 activation in the presence of TBK1 or OPTN as well as finding clinically translatable biomarkers to measure RIPK1 activity will be important steps towards identifying a broader ALS patient population that may benefit from this approach, and may open the door to the application of RIPK1-based therapy in other chronic neurodegenerative indications. 

    View all comments by Joseph Lewcock

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  1. Let ’Er RIP: ALS/FTD Variant Plus Aging Unleash Deadly Kinase


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