Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, Mifflin L, Pan L, Amin P, Li W, Shan B, Naito MG, Meng H, Li Y, Pan H, Aron L, Adiconis X, Levin JZ, Yankner BA, Yuan J. 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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Denali Therapeutics
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 …More
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.
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