DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice.
DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice.
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DHTKD1 缺乏会导致小鼠腓骨肌萎缩症。
DOI：
10.1128/mcb.00085-18
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发表时间：
2018
影响因子：
5.3
通讯作者：
Wang Zhu-Gang
中科院分区：
文献类型：
--
作者：
Xu Wang-Yang;Zhu Houbao;Shen Yan;Wan Ying-Han;Tu Xiao-Die;Wu Wen-Ting;Tang Lingyun;Zhang Hong-Xin;Lu Shun-Yuan;Jin Xiao-Long;Fei Jian;Wang Zhu-Gang
DHTKD 1是2-酮己二酸脱氢酶复合物的一部分，参与赖氨酸和色氨酸的催化。DHTKD 1突变阻断代谢途径，导致2-氨基己二酸和2-氧代己二酸尿症（AMOXAD），一种常染色体隐性遗传的先天性代谢紊乱。此外，我们以前发现的DHTKD 1无义突变导致Charcot-Marie-Tooth病（CMT）2 Q型，这是一种最常见的遗传性神经系统疾病，影响肌肉组织中的周围神经。然而，CMT 2 Q背后的全面分子机制仍然难以捉摸。在这里，我们发现Dhtkd 1 −/−小鼠模仿CMT 2表型的主要方面，其特征是肢体远端进行性无力和萎缩，伴有运动和感觉功能障碍，并伴有神经传导速度降低。此外，DHTKD 1缺乏导致严重的代谢异常和尿中2-酮己二酸（2-KAA）和2-氨基己二酸（2-AAA）水平的显著增加。进一步的研究表明2-KAA和2-AAA都能刺激胰岛素的合成和分泌。随后，升高的胰岛素通过上调早期生长反应2（Egr 2）的表达来调节许旺细胞中髓鞘蛋白零（Mpz）的转录，导致髓鞘结构损伤和轴突变性。最后，2-AAA喂养的小鼠确实复制了与CMT 2 Q表型相似的表型。总之，我们已经证明DHTKD 1的缺失通过MpzmRNA和蛋白零（P0）的失调引起CMT 2 Q样表型，这与DHTKD 1底物和胰岛素水平升高密切相关。这些发现进一步表明，除了线粒体功能不全的代谢紊乱在周围神经病变的发病机制中的重要作用。
DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations inDHTKD1block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation inDHTKD1that we identified previously causes Charcot-Marie-Tooth disease (CMT) type 2Q, one of the most common inherited neurological disorders affecting the peripheral nerves in the musculature. However, the comprehensive molecular mechanism underlying CMT2Q remains elusive. Here, we show thatDhtkd1−/−mice mimic the major aspects of CMT2 phenotypes, characterized by progressive weakness and atrophy in the distal parts of limbs with motor and sensory dysfunctions, which are accompanied with decreased nerve conduction velocity. Moreover, DHTKD1 deficiency causes severe metabolic abnormalities and dramatically increased levels of 2-ketoadipic acid (2-KAA) and 2-aminoadipic acid (2-AAA) in urine. Further studies revealed that both 2-KAA and 2-AAA could stimulate insulin biosynthesis and secretion. Subsequently, elevated insulin regulates myelin protein zero (Mpz) transcription in Schwann cells via upregulating the expression of early growth response 2 (Egr2), leading to myelin structure damage and axonal degeneration. Finally, 2-AAA-fed mice do reproduce phenotypes similar to CMT2Q phenotypes. In conclusion, we have demonstrated that loss of DHTKD1 causes CMT2Q-like phenotypes through dysregulation ofMpzmRNA and protein zero (P0) which are closely associated with elevated DHTKD1 substrate and insulin levels. These findings further indicate an important role of metabolic disorders in addition to mitochondrial insufficiency in the pathogenesis of peripheral neuropathies.