In a study recently published in Cell Reports, an IND team led by Dr. Daniel Mordes, together with collaborators in the Burlingame Lab, used human stem cell–derived neurons to understand how loss of the protein kinase TBK1 contributes to neurodegeneration. Harmful variants that impair TBK1 function are strongly associated with inherited forms of ALS (amyotrophic lateral sclerosis) and dementia. Using cutting-edge proteomic techniques, the team found that TBK1 sits at the crossroads of critical cellular pathways. In human neurons, TBK1 not only regulates autophagy factors that participate in protein waste management but also plays a key role in endo-lysosomal function. They additionally showed that neurons lacking TBK1 accumulate dysfunctional lysosomes, highlighting the central role of TBK1 in maintaining cellular homeostasis. This work provides a valuable phospho-protein reference atlas for human neurons that will be useful for additional studies on neurological disorders. Together, Smeyers et al. offer new insights into how TBK1 dysfunction triggers degeneration with a potential framework to develop new treatments.

Reference: Smeyers, J., Oses-Prieto, J. A., Yadanar, L., Wang, M., Iadarola, M., Lu, S., Wang, K. S., Watanabe, T. H., Debnath, J., Burlingame, A. L., & Mordes, D. A. (2025). Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks. Cell Reports, 44(11), 116494. doi:10.1016/J.CELREP.2025.116494