DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice.

Autor: Xu WY; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Research Center for Model Organisms, Shanghai, China., Zhu H; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Shen Y; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wan YH; Shanghai Research Center for Model Organisms, Shanghai, China., Tu XD; Shanghai Research Center for Model Organisms, Shanghai, China., Wu WT; Shanghai Research Center for Model Organisms, Shanghai, China., Tang L; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhang HX; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Model Organism Division, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Lu SY; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Model Organism Division, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Jin XL; Department of Pathology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Fei J; Shanghai Research Center for Model Organisms, Shanghai, China., Wang ZG; State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China zhugangw@shsmu.edu.cn.; Shanghai Research Center for Model Organisms, Shanghai, China.; Model Organism Division, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jazyk: angličtina
Zdroj: Molecular and cellular biology [Mol Cell Biol] 2018 Jun 14; Vol. 38 (13). Date of Electronic Publication: 2018 Jun 14 (Print Publication: 2018).
DOI: 10.1128/MCB.00085-18
Abstrakt: DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations in DHTKD1 block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation in DHTKD1 that 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 that Dhtkd1 -/- 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 of Mpz mRNA and protein zero (P 0 ) 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.
(Copyright © 2018 American Society for Microbiology.)
Databáze: MEDLINE
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