乙醛脱氢酶2抑制老年性神经元退行性病变的新机制

项目名称： 乙醛脱氢酶2抑制老年性神经元退行性病变的新机制

项目编号： No.31201037

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 余璐

作者单位： 中国人民解放军第四军医大学

项目金额： 24万元

中文摘要： 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。

中文关键词： 细胞衰老；羰基应激；自噬；ALDH2；SIRT1

英文摘要： 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 neur

英文关键词： Cellular Aging；Carbonyl stress；Autophagy；ALDH2；SIRT1