Traumatic brain injury (TBI) is the leading cause of mortality and disability in young people and may lead to the development of progressive neurodegeneration, such as that observed in chronic traumatic encephalopathy. We have recently found that the conformation-specific cis phosphorylated form of tau (cis P-tau) is a major early driver of neurodegeneration after TBI. However, not much is known about how cis P-tau is regulated in TBI. In this study, we demonstrated a novel critical role of death-associated protein kinase 1 (DAPK1) in regulating cis P-tau induction after TBI. We found that DAPK1 is significantly upregulated in mouse brains after TBI and subsequently promotes cis P-tau induction. Genetic deletion of DAPK1 in mice not only significantly decreases cis P-tau expression, but also effectively attenuates neuropathology development and rescues behavioral impairments after TBI. Mechanistically, DAPK1-mediated cis P-tau induction is regulated by the phosphorylation of Pin1 at Ser71, a unique prolyl isomerase known to control the conformational status of P-tau. Furthermore, pharmacological suppression of DAPK1 kinase activity dramatically decreases the levels of Pin1 phosphorylated at Ser71 as well as cis P-tau after neuronal stress. Thus, DAPK1 is a novel regulator of TBI that, in combination with its downstream targets, has a major impact on the development and/or outcome of TBI, and targeting DAPK1 might offer a potential therapeutic impact on TBI-related neurodegenerative diseases.

创伤性脑损伤 (TBI) 是导致年轻人死亡和残疾的主要原因，并可能导致进行性神经退行性变的发展，例如在慢性创伤性脑病中观察到的情况。我们最近发现，构象特异性顺式磷酸化形式的 tau ( cis P-tau) 是 TBI 后神经变性的主要早期驱动因素。然而，关于cis P-tau 如何在 TBI 中受到调控，我们知之甚少。在这项研究中，我们证明了死亡相关蛋白激酶 1 (DAPK1) 在调节TBI 后cis P-tau 诱导中的新关键作用。我们发现 DAPK1 在 TBI 后在小鼠大脑中显着上调并随后促进cisP-tau 诱导。小鼠中 DAPK1 的基因缺失不仅显着降低了cis P-tau 表达，而且还有效地减弱了神经病理学的发展并挽救了 TBI 后的行为障碍。从机制上讲，DAPK1 介导的顺式P-tau 诱导受 Pin1 在 Ser71 的磷酸化调节，这是一种独特的脯氨酰异构酶，已知可控制 P-tau 的构象状态。此外，DAPK1 激酶活性的药理学抑制显着降低了在 Ser71和顺式磷酸化的 Pin1 水平神经元应激后的 P-tau。因此，DAPK1 是一种新型的 TBI 调节剂，结合其下游靶点，对 TBI 的发展和/或结果产生重大影响，靶向 DAPK1 可能对 TBI 相关的神经退行性疾病产生潜在的治疗影响。