Our study reveals the mechanism by which dysfunction in metabolism may promote the activation of RIPK1: unlike ALS-associated genetic variants of OPTN and TBK1, which directly promote the activation of RIPK158, 59, NEK1 can indirectly modulate the activation of RIPK1 through regulating retromer trafficking and metabolism which in turn controls the levels of A20 by regulating the levels of acetyl-CoA. This evidence concerns the gene TBK1 and amyotrophic lateral sclerosis.