Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipperkinase (DLK) is an essential regulator of the progressive neurodegenerationthat occurs in amyotrophic lateral sclerosisand Alzheimer’s disease. We demonstrate that DLK/ c-Jun N-terminal kinasesignaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo. Furthermore, pharmacological inhibition of DLK activity was sufficient to attenuate the neuronal stress response and to provide functional benefit even in the presence of ongoing disease. These findings demonstrate that pathological activation of DLK is a conserved mechanism that regulates neurodegenerationand suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases.