scholarly journals Etiological Role of Dynamin in Charcot-Marie-Tooth Disease

10.5772/29046 ◽  
2012 ◽  
Author(s):  
Kohji Takei ◽  
Kenji Tanabe
Keyword(s):  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Etiological Role ◽  
Tooth Disease

Normal role of the low‐molecular‐weight neurofilament protein in mitochondrial dynamics and disruption in Charcot‐Marie‐Tooth disease

2011 ◽  
Vol 26 (3) ◽  
pp. 1194-1203 ◽  
Author(s):  
Benoit J. Gentil ◽  
Sandra Minotti ◽  
Madeleine Beange ◽  
Robert H. Baloh ◽  
Jean‐Pierre Julien ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Mitochondrial Dynamics ◽  
Low Molecular Weight ◽  
Neurofilament Protein ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

SIMPLEmutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation

2005 ◽  
Vol 25 (4) ◽  
pp. 372-383 ◽  
Author(s):  
Gulam Mustafa Saifi ◽  
Kinga Szigeti ◽  
Wojciech Wiszniewski ◽  
Michael E. Shy ◽  
Karen Krajewski ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Potential Role ◽  
Protein Product ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals SIRT2-knockdown Rescues GARS-induced Charcot-Marie-Tooth Neuropathy

2019 ◽  
Author(s):  
Chao Shen ◽  
Qian Qi ◽  
Yicai Qin ◽  
Dejian Zhou ◽  
Xinyuan Chen ◽  
...  
Keyword(s):  
Trna Synthetase ◽  
Nerve Degeneration ◽  
Loss Of Function ◽  
Wild Type ◽  
Partial Loss ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Underlying Mechanisms ◽  
Tooth Disease

AbstractCharcot-Marie-Tooth disease is the most common inherited peripheral neuropathy. Dominant mutations in glycyl-tRNA synthetase (GARS) gene cause peripheral nerve degeneration and lead to CMT disease type 2D. Mutations in GARS (GARSCMT2D) show partial loss-of-function features, suggesting that tRNA-charging deficits play a role in disease pathogenesis, but the underlying mechanisms are not fully understood. In this study we report that wild-type GARS tightly binds the NAD+-dependent deacetylase SIRT2 and inhibits its deacetylation activity, resulting in the hyperacetylated α-tubulin, the major substrate of SIRT2. Previous studies showed that acetylation of α-tubulin protects microtubules from mechanical breakage and keep axonal transportation. However, CMT2D mutations in GARS can not inhibit SIRT2 deacetylation, which leads to decrease acetylated α-tubulin and severe axonal transport deficits. Genetic reduction of SIRT2 in the Drosophila model rescues the GARS–induced axonal CMT neuropathy and extends the life span. Our findings demonstrate the pathogenic role of SIRT2-dependent α-tubulin deacetylation in mutant GARS-induced neuropathies and provide new perspectives for targeting SIRT2 as a potential therapy against hereditary axonopathies.

scholarly journals DHTKD1 deficiency causes Charcot-Marie-Tooth disease in mice

2018 ◽  
pp. MCB.00085-18 ◽  
Author(s):  
Wang-Yang Xu ◽  
Houbao Zhu ◽  
Yan Shen ◽  
Ying-Han Wan ◽  
Xiao-Die Tu ◽  
...  
Keyword(s):  
Insulin Biosynthesis ◽  
Charcot Marie Tooth ◽  
Structure Damage ◽  
Early Growth Response ◽  
Charcot Marie Tooth Disease ◽  
Tryptophan Catabolism ◽  
Protein Zero ◽  
Progressive Weakness ◽  
Tooth Disease

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 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, featured 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 reveal 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 the phenotypes like CMT2Q. In conclusion, we have demonstrated that loss of Dhtkd1 causes CMT2Q-like phenotypes through dysregulation of Mpz mRNA and P0 protein closely-associated with elevated DHTKD1 substrate and insulin levels. These findings further implicate an important role of metabolic disorders in addition to mitochondrial insufficiency in the pathogenesis of peripheral neuropathies.

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