Fig. 10

Schematic description of kinase signaling pathways in Amyotrophic lateral sclerosis. ALS genes encoding protein kinases, such as TBK1 and NEK1, affect the proteostasis process, autophagy, and DNA damage. TBK1 phosphorylates OPTN and p62, leading to autophagy clearance and thus ensuring efficient degradation of ubiquitinated mitochondria. TBK1 inactivates RIPK1 and loss of TBK1 boosts RIPK1 activation and promotes cell death. NEK1 mutations disable DNA damage response and its deficiency reduced the phosphorylation of VPS26B, leading to disruption of endosomal transport and further dysfunction of mitochondria and lysosome. Several kinases are involved in the phosphorylation of TDP-43 and others. The decrease of AKT activity in ALS leads to the upregulated GSK3β activity, contributing to TDP-43-induced axonal degeneration. c-Abl kinase mediates the accumulation of toxic FUS by phosphorylating FUS. Proteins abnormally aggregated alter the kinase signaling networks, eventually leading to cell death of motor neurons. This figure was created with BioRender.com