Nuclear TAR DNA-binding protein 43 A new target for amyotrophic lateral sclerosis treatment  

作　　者：Mei Zheng Yujie Shi Dongsheng Fan 

机构地区：[1]Department of Neurology, Peking University Third Hospital [2]School of Pharmaceutical Sciences, Peking University

出　　处：《Neural Regeneration Research》2013年第35期3284-3295,共12页中国神经再生研究（英文版）

基　　金：supported by the State Key Program of the Natural Science Foundation of China,No.81030019;the National Science Foundation for Young Scholars of China,No.81200969;the Peking University Third Hospital Scientific Research Foundation for Returned Scholars,No.73526-01

摘　　要：Abnormal TAR DNA-binding protein 43 （TDP-43） inclusion bodies can be detected in the degen- erative neurons of amyotrophic lateral sclerosis. In this study, we induced chronic oxidative stress injury by applying malonate to cultured mouse cortical motor neurons. In the later stages of the malonate insult, TDP-43 expression reduced in the nuclei and transferred to the cytoplasm. This was accompanied by neuronal death, mimicking the pathological changes in TDP-43 that are seen in patients with amyotrophic lateral sclerosis. Interestingly, in the early stages of the response to malonate treatment, nuclear TDP-43 expression increased, and neurons remained relatively intact, without inclusion bodies or fragmentation. Therefore, we hypothesized that the increase of nuclear TDP-43 expression might be a pro-survival factor against oxidative stress injury. This hypothesis was confirmed by an in vitro transgenic experiment, in which overexpression of wild type mouse TDP-43 in cultured cortical motor neurons significantly reduced malonate-induced neuronal death. Our findings suggest that the loss of function of TDP-43 is an important cause of neuronal degen- eration, and upregulation of nuclear TDP-43 expression might be neuroprotective in amyotrophic lateral sclerosis.Abnormal TAR DNA-binding protein 43 （TDP-43） inclusion bodies can be detected in the degen- erative neurons of amyotrophic lateral sclerosis. In this study, we induced chronic oxidative stress injury by applying malonate to cultured mouse cortical motor neurons. In the later stages of the malonate insult, TDP-43 expression reduced in the nuclei and transferred to the cytoplasm. This was accompanied by neuronal death, mimicking the pathological changes in TDP-43 that are seen in patients with amyotrophic lateral sclerosis. Interestingly, in the early stages of the response to malonate treatment, nuclear TDP-43 expression increased, and neurons remained relatively intact, without inclusion bodies or fragmentation. Therefore, we hypothesized that the increase of nuclear TDP-43 expression might be a pro-survival factor against oxidative stress injury. This hypothesis was confirmed by an in vitro transgenic experiment, in which overexpression of wild type mouse TDP-43 in cultured cortical motor neurons significantly reduced malonate-induced neuronal death. Our findings suggest that the loss of function of TDP-43 is an important cause of neuronal degen- eration, and upregulation of nuclear TDP-43 expression might be neuroprotective in amyotrophic lateral sclerosis.

关 键 词：neural regeneration neurodegenerative disease amyotrophic lateral sclerosis TAR DNA-bindingprotein 43 cortex motor neurons oxidative stress sodium malonate NEUROPROTECTION grants-supported paper NEURODEGENERATION 

分 类 号：R746[医药卫生—神经病学与精神病学]