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Axon degeneration is an early symptom of many neurodegenerative diseases.
Stopping or slowing down this process is considered to be an effective way to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's syndrome.
After a century of efforts by scientists, the biological mechanism that regulates neurodegeneration has gradually become clear.
In this mechanism, two proteins with opposite functions play a key regulatory role, NAD+synthetase—NMNAT2 and NAD+hydrolase—SARM1.
First, damage (including damage caused by physical, chemical, and genetic mutations) causes the degradation of NMNAT2.
Subsequently, SARM1 is activated to hydrolyze NAD+, eventually leading to axon degeneration.
However, how the degradation of NMNAT2 activates SARM1 has always been a problem that plagued scientists.
Some people believe that the accumulation of the substrate NMN caused by the degradation of NMNAT2 may be a molecular signal to activate SARM1; another part believes that the reduction of the product NAD+ caused by the degradation of NMNAT2 activates the SARM1 protein.
On March 2, 2021, the Bostjan Kobe Laboratory of the University of Queensland, Australia, in collaboration with Aaron DiAntonio, the Jeffrey Milbrandt team, and Griffith University Thomas Ve, published an article on Neuron in collaboration with Washington University in St.
Louis.
SARM1 is a metabolic sensor activated by an increased NMN/ The NAD+ ratio to trigger axon degeneration indicates that the accumulation of the substrate NMN caused by the degradation of NMNAT2 and the reduction of the product NAD+ jointly regulate the function of SARM1.Using X-ray crystallography, cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) and cell biology analysis, researchers in Kobe's laboratory found that small molecules NMN and NAD+ pass through the SARM1 N-terminal ARM domain.
(ARM domain) Direct contact to change the shape of the ARM domain, thereby affecting the NAD+ hydrolysis function of the C-terminal TIR domain (TIR domain).
In healthy axons, SARM1 remains inactive.
In this state, NAD+ may occupy the binding site on the ARM domain, forcing the ARM domain to maintain a stretched crescent shape, strengthening the interaction with the C-terminal TIR domain, forcing the TIR domains to separate from each other, and inhibiting the protein NAD+ hydrolysis function .
When damage causes NMNAT2 degradation to increase the ratio of NMN/NAD+ in axons, NMN replaces NAD+ and binds to the same position on the ARM domain, causing the ARM domain to stretch out and crescent structure to further curl, destroying and adjacent ARM, SAM and TIR Interaction between structural domains.
This allows the C-terminal TIR domain to be released, allowing TIR domains to assemble, turning on NAD+ hydrolysis, and ultimately causing axon degeneration.
The crystal structure of the ARM domain of NMN binding shows the important amino acid residues involved in NMN binding.
Site mutation technology and subsequent cell biological analysis confirmed that the binding of NMN effectively activates the function of SARM1 and turns on axon degeneration; when NMN binding is disturbed, the function of SARM1 is inhibited to varying degrees and slows down the axon degeneration.
Therefore, finding a method to inhibit SARM1 is likely to be the key to stopping or slowing down axon degeneration.
This discovery answers the debate that has plagued scientists for years about how NMNAT2 degradation activates SARM1; it provides valuable information for the subsequent design of drugs to inhibit SARM1 protein to treat neurodegenerative diseases.
Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
02.
009 Plate maker: Notes for reprinting on the eleventh [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.
Stopping or slowing down this process is considered to be an effective way to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's syndrome.
After a century of efforts by scientists, the biological mechanism that regulates neurodegeneration has gradually become clear.
In this mechanism, two proteins with opposite functions play a key regulatory role, NAD+synthetase—NMNAT2 and NAD+hydrolase—SARM1.
First, damage (including damage caused by physical, chemical, and genetic mutations) causes the degradation of NMNAT2.
Subsequently, SARM1 is activated to hydrolyze NAD+, eventually leading to axon degeneration.
However, how the degradation of NMNAT2 activates SARM1 has always been a problem that plagued scientists.
Some people believe that the accumulation of the substrate NMN caused by the degradation of NMNAT2 may be a molecular signal to activate SARM1; another part believes that the reduction of the product NAD+ caused by the degradation of NMNAT2 activates the SARM1 protein.
On March 2, 2021, the Bostjan Kobe Laboratory of the University of Queensland, Australia, in collaboration with Aaron DiAntonio, the Jeffrey Milbrandt team, and Griffith University Thomas Ve, published an article on Neuron in collaboration with Washington University in St.
Louis.
SARM1 is a metabolic sensor activated by an increased NMN/ The NAD+ ratio to trigger axon degeneration indicates that the accumulation of the substrate NMN caused by the degradation of NMNAT2 and the reduction of the product NAD+ jointly regulate the function of SARM1.Using X-ray crystallography, cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) and cell biology analysis, researchers in Kobe's laboratory found that small molecules NMN and NAD+ pass through the SARM1 N-terminal ARM domain.
(ARM domain) Direct contact to change the shape of the ARM domain, thereby affecting the NAD+ hydrolysis function of the C-terminal TIR domain (TIR domain).
In healthy axons, SARM1 remains inactive.
In this state, NAD+ may occupy the binding site on the ARM domain, forcing the ARM domain to maintain a stretched crescent shape, strengthening the interaction with the C-terminal TIR domain, forcing the TIR domains to separate from each other, and inhibiting the protein NAD+ hydrolysis function .
When damage causes NMNAT2 degradation to increase the ratio of NMN/NAD+ in axons, NMN replaces NAD+ and binds to the same position on the ARM domain, causing the ARM domain to stretch out and crescent structure to further curl, destroying and adjacent ARM, SAM and TIR Interaction between structural domains.
This allows the C-terminal TIR domain to be released, allowing TIR domains to assemble, turning on NAD+ hydrolysis, and ultimately causing axon degeneration.
The crystal structure of the ARM domain of NMN binding shows the important amino acid residues involved in NMN binding.
Site mutation technology and subsequent cell biological analysis confirmed that the binding of NMN effectively activates the function of SARM1 and turns on axon degeneration; when NMN binding is disturbed, the function of SARM1 is inhibited to varying degrees and slows down the axon degeneration.
Therefore, finding a method to inhibit SARM1 is likely to be the key to stopping or slowing down axon degeneration.
This discovery answers the debate that has plagued scientists for years about how NMNAT2 degradation activates SARM1; it provides valuable information for the subsequent design of drugs to inhibit SARM1 protein to treat neurodegenerative diseases.
Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
02.
009 Plate maker: Notes for reprinting on the eleventh [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.
