title: Nuclear TAR DNA-binding protein 43: A new target for amyotrophic lateral sclerosis treatment.
abstract: Abnormal TAR DNA-binding protein 43 (TDP-43) inclusion bodies can be detected in the degenerative 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 degeneration, and upregulation of nuclear TDP-43 expression might be neuroprotective in amyotrophic lateral sclerosis.
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Fan
keywords: TAR DNA-binding protein 43; amyotrophic lateral sclerosis; cortex; grantssupported paper; motor neurons; neural regeneration; neurodegeneration; neurodegenerative disease; neuroprotection; oxidative stress; sodium malonate