Table 1_Mechanistic insights into cadmium-related premature aging in Drosophila model.docx

The intricate and multifaceted relationship between environmental pollutants, particularly heavy metals such as cadmium, and human health has been extensively documented, with a significant focus on their neurotoxic effects. Notably, the connection between cadmium exposure and Alzheimer’s disease is becoming increasingly evident, prompting a deeper investigation into the underlying mechanisms at play. Despite the growing body of evidence linking cadmium to neurodegeneration and although harmful molecular activities of cadmium in cells have been demonstrated, the precise molecular mechanism induced by this toxic metal within neuronal cells remains largely enigmatic. This study aims to shed light on these mechanistic processes by utilizing Drosophila melanogaster, a widely recognized model organism in neurogenetics, as our experimental framework. Through a carefully designed approach, we simulated chronic exposure to cadmium, which allowed us to observe the resulting effects on the flies over time. Our findings revealed that chronic cadmium exposure led to premature aging in flies, characterized by neurodegeneration and an exacerbation of complex neurological phenotypes. Notably, these included significant impairments in learning and memory, which are critical cognitive functions often compromised in neurodegenerative conditions. With the aim of exploring the mechanistic underpinnings of these observations, we determined that cadmium impairs RNP formation and could disrupt the delicate process of liquid–liquid phase separation within neuronal cells. This disruption appears to play a pivotal role in initiating the cascade of events that contribute to neurodegeneration. Liquid–liquid phase separation is essential for the proper organization of cellular components and the maintenance of neuronal health; thus, cadmium’s interference in this process may provide a crucial insight into its neurotoxic effects.

环境污染物，尤其是镉（cadmium）这类重金属，与人类健康之间复杂且多维度的关联已被广泛研究，其神经毒性效应是重点关注方向。值得注意的是，镉暴露与阿尔茨海默病（Alzheimer’s disease）之间的关联愈发明确，这推动学界对其潜在作用机制展开更深入的探究。尽管已有越来越多证据证实镉与神经退行性变存在关联，且镉在细胞内的有害分子活性已被探明，但该有毒金属在神经元细胞内诱导的确切分子机制仍尚不明晰。本研究以神经遗传学领域广泛认可的模式生物——黑腹果蝇（Drosophila melanogaster）作为实验框架，旨在阐明上述机制过程。通过精心设计的实验方案，我们模拟了镉的慢性暴露，从而能够长时间观察果蝇受到的影响。研究结果显示，慢性镉暴露会导致果蝇提前衰老，表现为神经退行性变以及复杂神经表型的恶化。尤为关键的是，这些表型包括学习与记忆功能的显著损伤——而学习记忆正是神经退行性疾病中常受损害的关键认知功能。为探究上述观察结果的机制基础，我们进一步发现，镉会损害RNP形成（RNP formation），并可能扰乱神经元细胞内精细的液液相分离（liquid–liquid phase separation）过程。这种紊乱似乎在启动引发神经退行性变的级联反应中发挥核心作用。液液相分离对于细胞组分的正常组装以及神经元健康的维持至关重要，因此镉对该过程的干扰或许能为解释其神经毒性效应提供关键线索。