Xu Chenchen, Liu Songyang, Cheng Nan, Han Yongsheng, Wang Xinheng
Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China.
The Affiliated Hospital of Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China.
Front Neurosci. 2024 Nov 25;18:1447304. doi: 10.3389/fnins.2024.1447304. eCollection 2024.
Synaptic efficacy is critical for memory formation and consolidation. Accumulating evidence suggest that synapses are impaired during Wilson's disease (WD), contributing to neuronal dysfunction and cognitive decline. WD is a prototypical condition among the copper metabolism disorders. Cognitive impairment is a common feature of affected patients with neurological symptoms, presenting as memory deficits, decreased cognitive flexibility, and impaired learning capabilities. These cognitive deficits can significantly impact the quality of life, affecting work and academic performance. However, the mechanisms mediating the inhibitory synaptic dysfunction in WD are incompletely understood. We investigated the effects of the double-stranded RNA-dependent protein kinase/eukaryotic initiation factor 2α (PKR/eIF2α) pathway on synaptic structure and function in WD using a murine model, toxic milk (TX mice). During mouse open-field tests, we noted a substantial rise in the mobility/immobility ratio among WD model animals compared to that in WT mice. Additionally, WD mice exhibited diminished central area exploration, as evidenced by reduced travel distance. Moreover, they displayed prolonged escape latency in the Barnes maze, suggesting that chronic copper accumulation is associated with neuropsychiatric alterations and cognitive impairment. We also found a decrease in the expression of synapse-associated proteins (synapsin 1, synaptophysin, postsynaptic density protein-93 [PSD93], postsynaptic density protein-95 [PSD95]), and vesicle-associated membrane protein2 [VAMP2]) besides abnormal neurotransmitter levels (including glutamate and GABA), indicating the presence of synaptic dysfunction in TX mice. Inhibiting PKR via C16 prevented these changes, suggesting that dysfunctional cognition is associated with the PKR/eIF2α pathway. We also observed changes in synapses, vesicles, dendritic spine density, and dendritic length that were associated with the presence of cognitive dysfunction. Further investigation revealed that C16 treatment decreased the TUNEL-positive cell numbers in the hippocampus of TX mice and prevented 8-OHdG-induced synaptic dysfunction. Results suggest that PKR downregulation prevents copper-induced synaptic dysfunction in the murine WD model. Therefore, targeting PKR pharmacologically may be a potential therapeutic strategy for treating the copper-induced neuropathology of patients with WD.
突触效能对记忆形成和巩固至关重要。越来越多的证据表明，威尔逊病（WD）期间突触受损，导致神经元功能障碍和认知能力下降。WD是铜代谢紊乱中的典型病症。认知障碍是有神经症状的受影响患者的常见特征，表现为记忆缺陷、认知灵活性降低和学习能力受损。这些认知缺陷会显著影响生活质量，影响工作和学业表现。然而，WD中介导抑制性突触功能障碍的机制尚不完全清楚。我们使用毒性乳鼠模型（TX小鼠）研究了双链RNA依赖性蛋白激酶/真核起始因子2α（PKR/eIF2α）通路对WD突触结构和功能的影响。在小鼠旷场试验中，我们注意到与野生型小鼠相比，WD模型动物的活动/静止比率大幅上升。此外，WD小鼠对中央区域的探索减少，行进距离缩短证明了这一点。此外，它们在巴恩斯迷宫中的逃避潜伏期延长，表明慢性铜积累与神经精神改变和认知障碍有关。我们还发现，除了神经递质水平异常（包括谷氨酸和γ-氨基丁酸）外，突触相关蛋白（突触素1、突触囊泡蛋白、突触后致密蛋白-93 [PSD93]、突触后致密蛋白-95 [PSD95]）和囊泡相关膜蛋白2 [VAMP2]）的表达也降低，表明TX小鼠存在突触功能障碍。通过C16抑制PKR可防止这些变化，表明功能失调的认知与PKR/eIF2α通路有关。我们还观察到与认知功能障碍相关的突触、囊泡、树突棘密度和树突长度的变化。进一步研究发现，C16处理可减少TX小鼠海马体中TUNEL阳性细胞数量，并防止8-羟基脱氧鸟苷诱导的突触功能障碍。结果表明，PKR下调可预防小鼠WD模型中铜诱导的突触功能障碍。因此，药理学上靶向PKR可能是治疗WD患者铜诱导神经病理学的潜在治疗策略。
