"Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD- associated autophagy networks"

"Loss-of-function variants in TBK1, encoding a serine/threonine protein kinase, are stronglyassociated with sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporaldementia (FTD). However, the targets of TBK1 in neurons are unknown, and howhaploinsufficiency for TBK1 leads to age-related neurodegeneration remains unresolved. Here,we utilized sets of isogenic induced pluripotent stem cells (iiPSCs) with loss of TBK1 or loss ofoptineurin (OPTN) for quantitative proteomics and phospho-proteomics across tens of thousandsof phospho-sites in proliferating stem cells and induced excitatory neurons. We found that TBK1sustains the abundance and phosphorylation of its interacting adapter proteins, AZI2/NAP1,TBKBP1, and TANK1, in the cellular context of neurons. Moreover, TBK1 regulates thephosphorylation of selective autophagy proteins, particularly at novel phospho-serine residueswithin cargo receptors, and endo-lysosomal pathways, including the late-endosome GTPaseRAB7A, in human neurons. Additionally, we observed that the disease-associated TBK1 G217Rvariant acts as a phospho-protein quantitative trait locus (ppQTL) for the phosphorylation statusof familial ALS-associated proteins p62/SQSTM1 and OPTN, as well as GABARAPL2, an Atg8-family autophagy protein. Furthermore, we demonstrate that TBK1 is required for neuriteoutgrowth and lysosomal function. Finally, we provide a census of the phospho-proteome innascent human neurons for further dissection of protein phosphorylation in neural-enrichedproteins, such as tau, in neurological and psychiatric disorders. These studies provide a globalview of TBK1 as a central point of convergence in ALS/FTD-linked endo-lysosomal networks thatact in a cell-autonomous manner to maintain protein homeostasis in neurons."