Co-occurrence of TDP-43 mislocalization with reduced activity of an RNA editing enzyme, ADAR2, in aged mouse motor neurons.
Co-occurrence of TDP-43 mislocalization with reduced activity of an RNA editing enzyme, ADAR2, in aged mouse motor neurons.
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DOI：
10.1371/journal.pone.0043469
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kwak S
中科院分区：
文献类型：
--
作者：
Hideyama T;Teramoto S;Hachiga K;Yamashita T;Kwak S
脊髓运动神经元中的TDP-43病理学是散发性肌萎缩侧索硬化症（ALS）的神经病理学标志，并且最近已显示与散发性ALS患者的运动神经元中作用于RNA 2的称为腺苷脱氨酶（ADAR 2）的RNA编辑酶的下调密切相关。由于TDP-43病理在老年患者的大脑中更常见，我们研究了小鼠运动神经元中TDP-43定位和ADAR 2活性的年龄相关变化。我们发现，ADAR 2是发展上调，其mRNA表达水平进行性下降，在老年小鼠的脊髓。运动神经元通常表现出核ADAR 2和TDP-43免疫反应性，而老年小鼠的快疲劳运动神经元表现出ADAR 2和异常TDP-43定位的损失。重要的是，这些运动神经元表达了大量的Q/R位点未编辑的AMPA受体亚基2（GluA 2）mRNA。由于未编辑的GluA 2的表达已被证明是在运动神经元中观察到的致死性分子异常，因此这些结果表明，ADAR 2活性的年龄相关性降低在衰老中起着机械作用，并且是ALS的风险因素之一。
TDP-43 pathology in spinal motor neurons is a neuropathological hallmark of sporadic amyotrophic lateral sclerosis (ALS) and has recently been shown to be closely associated with the downregulation of an RNA editing enzyme called adenosine deaminase acting on RNA 2 (ADAR2) in the motor neurons of sporadic ALS patients. Because TDP-43 pathology is found more frequently in the brains of elderly patients, we investigated the age-related changes in the TDP-43 localization and ADAR2 activity in mouse motor neurons. We found that ADAR2 was developmentally upregulated, and its mRNA expression level was progressively decreased in the spinal cords of aged mice. Motor neurons normally exhibit nuclear ADAR2 and TDP-43 immunoreactivity, whereas fast fatigable motor neurons in aged mice demonstrated a loss of ADAR2 and abnormal TDP-43 localization. Importantly, these motor neurons expressed significant amounts of the Q/R site-unedited AMPA receptor subunit 2 (GluA2) mRNA. Because expression of unedited GluA2 has been demonstrated as a lethality-causing molecular abnormality observed in the motor neurons, these results suggest that age-related decreases in ADAR2 activity play a mechanistic role in aging and serve as one of risk factors for ALS.
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影响因子：
4.4
作者：
Atsuta, Naoki;Watanabe, Hirohisa;Sobue, Gen
通讯作者：
Sobue, Gen
影响因子：
2.5
作者：
KANDA, K;HASHIZUME, K
通讯作者：
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DOI：
10.1016/j.devbrainres.2003.11.008
发表时间：
2004-01-31
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
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作者：
Kawahara, Y;Ito, K;Kwak, S
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
3.4
作者：
DENGLER, R;KONSTANZER, A;STRUPPLER, A
通讯作者：
STRUPPLER, A