HSP90通过LAMP2A调控伴侣蛋白介导自噬诱导铁死亡在抑郁症发生中的可能机制研究

铁死亡已成为神经系统疾病领域的研究热点，但在抑郁症中尚无明确报道。临床研究发现抑郁症患者常伴有缺铁性贫血，脑组织中可见铁沉积。近期研究提示伴侣蛋白介导自噬（CMA)依赖的铁死亡可能参与了抑郁症的发生，且热休克蛋白HSP90可通过调控CMA受体LAMP2A进而影响神经元的内稳态。本项目拟建立可靠的由Erastin诱导铁死亡介导的急性抑郁模型并对模型进行评价；探讨抑郁模型大鼠前额叶皮质及海马脑区CMA和铁死亡的水平变化；进一步通过改变LAMP2A水平和抑制HSP90活性,探讨CMA依赖性铁死亡通路和神经可塑性的改变，证明HSP90对LAMP2A的调控关系；并在原代神经元细胞水平进行体外验证。由此从自噬诱导铁死亡所致神经元的内稳态的变化的新角度探索抑郁症的可能发病机制，尝试为抑郁症的病因研究开辟新的方向，为抑郁症的防治提供新的策略与靶点。

Ferroptosis has attracted increasing attention in neurological disorders .In depression, however, there is hardly any research achievement. Clinical studies have found that patients with depression are often accompanied by iron deficiency anemia and iron deposition in the brain is observed. Recent researches demonstrated that CMA- dependent ferroptosis is involved in the development of depression and HSP90 affects neuronal homeostasis through regulating the CMA receptor LAMP2A.This research aims to establish a reliable Erastin - induced ferroptosis - mediated animal model of acute depression and evaluate the performance. On this basis, investigate the levels of CMA and ferroptosis in the prefrontal cortex and hippocampus of depressed rats. Furthermore, by changing LAMP2A expression level and inhibiting HSP90 activity, we may discuss the changes of CMA-dependent ferroptosis pathway as well as the neuroplasticity and decipher the regulatory relationship between HSP90 and LAMP2A. Finally, all these results will be verified in primary neurons. Therefore, from the new perspective of autophagy inducing ferroptosis generateing alterations in the neurohomeostasis to explored the possible pathogenesis of depression, we attempt to blaze a new trail for the study of the etiology of depression, meanwhile, provide new strategies and targets for the prevention and treatment of depression.