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The nervous system is divided into the central nervous system and the peripheral nervous system.
Peripheral neurological diseases refer to diseases that originate from damage to the structure or function of the peripheral nervous system.
Among them, peroneal muscular atrophy is the most common genetic disease of the peripheral nervous system.
It was first reported by Charcot, Marie and Tooth in 1886, so it was also named Charcot-Marie-Tooth disease (CMT).
The incidence of CMT is about 1/2500, and the total number of patients worldwide currently exceeds 2.
8 million.
In fact, because CMT patients have relatively mild symptoms and are not life-threatening in the short term, the actual number of patients far exceeds this value.
The main characteristic of CMT is the loss of motor function caused by motor neuron degeneration, and its occurrence is closely related to specific gene mutations.
At present, more than 100 gene mutations have been found to be related to the disease.
The largest type of gene family encodes aminoacyl tRNA synthetase (aaRS), including GlyRS, TyrRS, HisRS, TrpRS and AlaRS.
The mechanism of the disease is still unclear, and effective treatments are currently lacking [1].
In 2019, research by Dr.
Litao Sun and others (see BioArt report: PNAS | Dr.
Litao Sun and others discuss the pathogenic mechanism of genetic diseases of the nervous system caused by mutations in the aminoacyl tRNA synthetase gene) showed that many HisRSCMT mutants do not affect HisRS in vivo Catalytic activity, and the level of tRNAHis aminoacylation was not affected.
However, many different biophysical methods such as small-angle scattering (SAXS), dynamic biosensor (switchSENSE), and hydrogen deuterium displacement-mass spectrometry (HDX-MS) found that almost all HisRSCMT mutants can cause changes in the conformation of HisRS protein [2 ].
In order to verify whether all aaRSCMT mutants will cause protein conformation changes and identify their potential binding substrates, Dr.
Litao Sun will publish on PNAS again on March 30, 2021 entitled "CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS" Research papers.
The study further found that most of the AlaRSCMT mutants did not affect their catalytic activity, especially the R329H mutant, which is the most widely distributed and most severe phenotype, and the aminoacylation level of tRNAAla in patients was not affected.
In addition, the AlaRSCMT mutant causes a change in the conformation of the AlaRS protein, and the mutant located in the catalytic region of AlaRS can specifically bind to neuropilin1 (Nrp1).
The above work shows that the CMT disease caused by aaRS mutation is not entirely caused by simple aminoacylation loss (loss of function).
Some aaRS gene mutations can cause changes in protein conformation and enable them to obtain binding to new target molecules.
The ability (gain of function), and the substrates that different mutants of different aaRS bind to are also different.
This feature also reflects the complexity of the pathogenic mechanism of CMT [3].
In view of this, Dr.
Sun Litao published a review titled "Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: a gain or a loss?" in the Journal of Neurochemistry [1], systematically expounding that gene mutations in aaRS family members cause The research progress of CMT disease, and the potential treatment of such diseases are discussed, in order to achieve precise treatment of such complex diseases (for details, see BioArt report: Non-classical function of a classic enzyme). Dr.
Litao Sun is currently a professor and doctoral supervisor in the School of Public Health, Sun Yat-sen University (Shenzhen).
He is mainly engaged in protein translation, post-translational modification and molecular mechanism research of related diseases; aaRS-related viral infection and immune regulation research, etc.
He has published more than ten papers in journals such as Nature, Nat.
Struct.
Mol.
Biol.
, J.
Am.
Chem.
Soc, Proc.
Natl.
Acad.
Sci.
USA and Nat.
Commun.
Warmly welcome aspiring young people to join this young, free, creative and team spirit team.
For details, please refer to: http://phs.
sysu.
edu.
cn/zh-hans/teacher/181 Reprint Instructions [Non-original article 】The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated. Platemaker: Qijiang Reference 1.
Zhang H, Zhou ZW, Sun L.
(2020).
Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: A gain or a loss? Journal of Neurochemistry, DOI: 10.
1111/jnc.
152492.
Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL.
(2019).
CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.
Proc Natl Acad Sci USA, DOI: 10.
1073/pnas.
19082881163.
Sun L, Wei N, Kuhle B, Blocquel D, Novick S, Matuszek Z, Zhou H , He W, Zhang J, Weber T, Horvath R, Latour P, Pan T, Schimmel P, Griffin PR, Yang XL.
(2021).
CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS.
Proc Natl Acad Sci USA, DOI: 10.
1073/pnas.
2012898118
Peripheral neurological diseases refer to diseases that originate from damage to the structure or function of the peripheral nervous system.
Among them, peroneal muscular atrophy is the most common genetic disease of the peripheral nervous system.
It was first reported by Charcot, Marie and Tooth in 1886, so it was also named Charcot-Marie-Tooth disease (CMT).
The incidence of CMT is about 1/2500, and the total number of patients worldwide currently exceeds 2.
8 million.
In fact, because CMT patients have relatively mild symptoms and are not life-threatening in the short term, the actual number of patients far exceeds this value.
The main characteristic of CMT is the loss of motor function caused by motor neuron degeneration, and its occurrence is closely related to specific gene mutations.
At present, more than 100 gene mutations have been found to be related to the disease.
The largest type of gene family encodes aminoacyl tRNA synthetase (aaRS), including GlyRS, TyrRS, HisRS, TrpRS and AlaRS.
The mechanism of the disease is still unclear, and effective treatments are currently lacking [1].
In 2019, research by Dr.
Litao Sun and others (see BioArt report: PNAS | Dr.
Litao Sun and others discuss the pathogenic mechanism of genetic diseases of the nervous system caused by mutations in the aminoacyl tRNA synthetase gene) showed that many HisRSCMT mutants do not affect HisRS in vivo Catalytic activity, and the level of tRNAHis aminoacylation was not affected.
However, many different biophysical methods such as small-angle scattering (SAXS), dynamic biosensor (switchSENSE), and hydrogen deuterium displacement-mass spectrometry (HDX-MS) found that almost all HisRSCMT mutants can cause changes in the conformation of HisRS protein [2 ].
In order to verify whether all aaRSCMT mutants will cause protein conformation changes and identify their potential binding substrates, Dr.
Litao Sun will publish on PNAS again on March 30, 2021 entitled "CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS" Research papers.
The study further found that most of the AlaRSCMT mutants did not affect their catalytic activity, especially the R329H mutant, which is the most widely distributed and most severe phenotype, and the aminoacylation level of tRNAAla in patients was not affected.
In addition, the AlaRSCMT mutant causes a change in the conformation of the AlaRS protein, and the mutant located in the catalytic region of AlaRS can specifically bind to neuropilin1 (Nrp1).
The above work shows that the CMT disease caused by aaRS mutation is not entirely caused by simple aminoacylation loss (loss of function).
Some aaRS gene mutations can cause changes in protein conformation and enable them to obtain binding to new target molecules.
The ability (gain of function), and the substrates that different mutants of different aaRS bind to are also different.
This feature also reflects the complexity of the pathogenic mechanism of CMT [3].
In view of this, Dr.
Sun Litao published a review titled "Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: a gain or a loss?" in the Journal of Neurochemistry [1], systematically expounding that gene mutations in aaRS family members cause The research progress of CMT disease, and the potential treatment of such diseases are discussed, in order to achieve precise treatment of such complex diseases (for details, see BioArt report: Non-classical function of a classic enzyme). Dr.
Litao Sun is currently a professor and doctoral supervisor in the School of Public Health, Sun Yat-sen University (Shenzhen).
He is mainly engaged in protein translation, post-translational modification and molecular mechanism research of related diseases; aaRS-related viral infection and immune regulation research, etc.
He has published more than ten papers in journals such as Nature, Nat.
Struct.
Mol.
Biol.
, J.
Am.
Chem.
Soc, Proc.
Natl.
Acad.
Sci.
USA and Nat.
Commun.
Warmly welcome aspiring young people to join this young, free, creative and team spirit team.
For details, please refer to: http://phs.
sysu.
edu.
cn/zh-hans/teacher/181 Reprint Instructions [Non-original article 】The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated. Platemaker: Qijiang Reference 1.
Zhang H, Zhou ZW, Sun L.
(2020).
Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: A gain or a loss? Journal of Neurochemistry, DOI: 10.
1111/jnc.
152492.
Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL.
(2019).
CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.
Proc Natl Acad Sci USA, DOI: 10.
1073/pnas.
19082881163.
Sun L, Wei N, Kuhle B, Blocquel D, Novick S, Matuszek Z, Zhou H , He W, Zhang J, Weber T, Horvath R, Latour P, Pan T, Schimmel P, Griffin PR, Yang XL.
(2021).
CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS.
Proc Natl Acad Sci USA, DOI: 10.
1073/pnas.
2012898118
