Here, we observed that the interaction between TBK1 and its several substrates, including IRF3, p62 and OPTN, were greatly disrupted by UBQLN2 mutations, implying that impaired TBK1 may contribute a role in the pathogenesis of UBQLN2-related ALS/FTD. The gene discussed is TBK1; the disease is amyotrophic lateral sclerosis.