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 zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer’s disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling 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 neurodegeneration and suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases.

慢性神经退行性疾病的特征包括进行性突触损失和神经元细胞死亡，但构成这些过程基础的细胞途径在很大程度上仍未确定。我们提供的证据表明，双亮氨酸拉链激酶（DLK）是在肌萎缩性侧索硬化症和阿尔茨海默氏病中发生的进行性神经变性的重要调节剂。我们证明，在患有这些疾病的小鼠模型和人类患者中，DLK / c-Jun N末端激酶信号传导增加，而DLK的基因缺失可防止轴突变性，神经元丢失和体内功能下降。此外，对DLK活性的药理抑制作用足以减弱神经元应激反应，即使在进行性疾病的情况下也能提供功能性益处。