乙醛脱氢酶2抑制老年性神经元退行性病变的新机制

Given the severe situation of population aging in china, it is critical to clarify the mechanism and control measures of age-related neurodegenerative diseases. Lipid peroxidation leads to the formation of highly reactive unsaturated aldehydes which is involved in neuronal damage and abnormal protein folding. Our recently study showed that unsaturated aldehydes leads to the age-dependent accumulation of neuronal protein carbonylation damage. Moreover, the level of neuronal autophagy was negatively correlated with age. Our previously study demonstrated that mitochondrial aldehyde dehydrogenase (ALDH2) is capable of rapidly remove intracellulare toxic aldehyde, furthermore, we reported firstly that ALDH2 is also involved in regulating the level of autophagy. Here, we hypothesis, aldehyde toxic accumulation induced abnormal proteins concentrated in neuron and age-dependent neuronal autophagy decline form a concatenate of vicious stress, which vicious cycle could lead to neurodegeneration. ALDH2 can dual function as detoxification the accumulation of toxic aldehyde and regulation of neuronal autophagy. To test our hypothesis, this study intends to focus on the intermodulation mechanism between aldehyde toxic accumulation and autophagy decline in aging neurons. Transgenic mouse model was utilized to examine the neuroprotection of ALDH2 in neuronal senescence. We also would investigate the therapeutical tactics of ALDH2 as a new target for neurodegeneration. This study will enrich the mechanism of neuronal senescence and understanding of ALDH2, suggestion a new concept for slow brain aging in ordr to extening healthy life of elder.

我国人口老龄化形势严峻，阐明老年性神经退行性病变的发生机制及防治措施意义重大。脂质过氧化产生的不饱和醛参与了神经元损伤以及蛋白质折叠异常。我们的研究首次发现，醛引起的神经元蛋白质羰基化损伤出现增龄性积累；而老化神经元自噬水平与年龄呈负相关。此外，重要的醛类代谢酶乙醛脱氢酶2(ALDH2)可迅速清除醛毒性，并且我们首次发现ALDH2还参与调节细胞自噬水平。据此假设，醛毒积累导致异常蛋白堆积和老化神经元自噬衰退相伴形成连锁应激导致老化神经元退行性损伤；调节ALDH2可能兼顾实现清除醛毒积累以及调节自噬的双重保护作用。基于上述发现，本研究拟围绕衰老神经元醛类毒性与自噬的互调机制，采用转基因动物模型，明确ALDH2对老化神经元的保护机制，进而探讨以ALDH2为靶点防治老年性神经元退行性病变的策略。本研究将丰富神经元老化的发生机制和拓展对ALDH2的认识，为延长老年健康寿命期，延缓脑衰老开启新思路。

细胞衰老常伴随自噬能力减退可引发或加重异常蛋白堆积。然而，自噬减退与异常蛋白堆积在神经元和心肌（终末细胞）衰老过程中的互调机制尚不明确。本研究从羰基应激入手，探讨终末细胞中蛋白质羰基化损伤与自噬减退的相互关系，并分析能的关键信号机制。目前已完成研究内容，研究结果证实：与对照组细胞相比，衰老细胞中(4-HNE等)活性羰基类物质显著增多，导致蛋白质羰基化程度显著加重；衰老细胞中的自噬能力显著减退，自噬流受阻；衰老导致细胞醛类代谢酶-乙醛脱氢酶2（ALDH2）活性显著减退；证实SIRT1是羰基应激的靶点分子，SIRT1羰基化失活导致FoxO1等自噬相关信号功能减退。在整体动物实验中证实采用ALDH2激动剂Alda-1处理可有效抑制SIRT1的羰基化，改善SIRT1活性，促进细胞自噬。我们证实衰老终末细胞中羰基应激程度显著加重，细胞自噬能力显著减退，两者相互促进形成恶性循环。激活ALDH2可有效抑制SIRT1的羰基化失活进而促进细胞自噬能力的改善。本研究为终末细胞衰老过程中蛋白质损伤与降解的动态平衡提供了新的联系机制。