Amyotrophic lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons in the central nervous system. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) account for approximately in 20% of familial ALS cases. The pathological mechanisms underlying the toxicity induced by mutated SOD1 are still unknown. However, it has been hypothesized that oxidative stress (OS) has a crucial role in motor neuron degeneration in ALS patients. Moreover, it has been described that SOD1 mutation interferes expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a protective key modulator against OS and reactive oxygen species (ROS) formation.

The protective effect of pituitary adenylate cyclase-activating peptide (PACAP) has been demonstrated in various neurological disorders, including ALS. Some of its effects are mediated by the stimulation of an intracellular factor known as activity-dependent protein (ADNP). The role of PACAP-ADNP axis on mutated SOD1 motor neuron degeneration has not been explored, yet. The present study aimed to investigate whether PACAP prevented apoptotic cell death induced by growth factor deprivation through ADNP activation and whether the peptidergic axis can counteract the OS insult.

By using an in vitro model of ALS, we demonstrated that PACAP by binding to PAC1 receptor (PAC1R) prevented motor neuron death induced by serum deprivation through induction of the ADNP expression via PKC stimulation. Furthermore, we have also demonstrated that the PACAP/ADNP axis counteracted ROS formation by inducing translocation of the Nfr2 from the cytoplasm to the nucleus. In conclusion, our study provides new insights regarding the protective role of PACAP-ADNP in ALS.

肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是中枢神经系统运动神经元进行性退化。编码铜/锌超氧化物歧化酶 (SOD1) 的基因突变约占家族性 ALS 病例的 20%。SOD1 突变引起的毒性的病理机制仍不清楚。然而，据推测氧化应激 (OS) 在 ALS 患者运动神经元变性中起着至关重要的作用。此外，据报道，SOD1 突变会干扰核因子红细胞 2 相关因子 2 (Nrf2) 的表达，Nrf2 是针对 OS 和活性氧 (ROS) 形成的保护性关键调节剂。

垂体腺苷酸环化酶激活肽 (PACAP) 的保护作用已在多种神经系统疾病（包括 ALS）中得到证实。它的一些作用是通过刺激称为活性依赖性蛋白（ADNP）的细胞内因子介导的。PACAP-ADNP 轴在突变 SOD1 运动神经元变性中的作用尚未被探索。本研究旨在探讨 PACAP 是否可以通过 ADNP 激活来阻止生长因子剥夺诱导的细胞凋亡，以及肽能轴是否可以抵消 OS 损伤。

通过使用 ALS 的体外模型，我们证明 PACAP 通过与 PAC1 受体 (PAC1R) 结合，通过PKC 刺激诱导 ADNP 表达，防止血清剥夺引起的运动神经元死亡。此外，我们还证明 PACAP/ADNP 轴通过诱导 Nfr2 从细胞质易位到细胞核来抵消 ROS 的形成。总之，我们的研究提供了有关 PACAP-ADNP 在 ALS 中的保护作用的新见解。