Current Biology Sheng Zuhang's team reveals a new mechanism for neuronal axon damage response signals to regulate energy metabolism and promote survival and regeneration after injury

Responsibility Editor | The maintenance of nervous system function requires a large amount of energy (ATP).
Mitochondria produce ATP through oxidative phosphorylation, which is the main source of neuronal cell energy
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Due to the highly polar structure of neurons and the limited diffusion capacity of ATP in axons, the bidirectional transport of mitochondria in axons is essential to maintain the energy homeostasis at the ends of neuronal axons
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Once mature neuron cells are acutely damaged, the function and transport of mitochondria in the axons will be abnormal, and the damaged axons will face the pressure of extreme loss of energy, which will eventually lead to axon degeneration and failure to regenerate
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Reports in recent years have shown that many proteins do not need to be synthesized in the cell body and then transported to the axon, but are directly synthesized inside the axon (axonal protein synthesis), so as to function more quickly and efficiently to ensure the function and function of neurons.
Completeness
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Therefore, it is of great significance to study how mature neurons respond to injury stimuli in axons and regulate energy metabolism
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On June 3, 2021, the National Institute of Health (NIH) Sheng Zuhang team published a research paper entitled Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia in Current Biology
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The study found that the AKT-PAK5 signaling pathway is a new mechanism for the response to damage within axons of mature neurons.
By improving the transport efficiency of mitochondria after axon injury, it regulates the maintenance of energy homeostasis after axon injury
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Activating this signal pathway significantly promotes the recovery of energy metabolism of mature neuron axons after injury, and then helps axons survive and regenerate after injury
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The study firstly used microfluidic devices to establish stimulation models that mimic cerebral ischemia and axonal injury in vitro, combined with puromycin labeling and ortho-site connection technology (Puro-PLA), and found that neurons specifically expressed The protein synthesis of kinase PAK5 in axons was significantly increased after being stimulated by two different injuries
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Using the fluorescent probe GO-ATeam2 to label the ATP levels in axons in real time, it was found that activating the PAK5 signaling pathway can significantly restore the energy homeostasis of damaged axons
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STED observations with ultra-high resolution microscopy revealed that PAK5 kinase is localized on the surface of axon mitochondria, and its expression level gradually decreases with the maturation of neurons, which is consistent with the weakening trend of mitochondrial motility in axons
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After activating the PAK5 signal, the transport of axon mitochondria in three different systems, including central system neurons cultured in vitro, dorsal root ganglion (DRG) neurons, and ex vivo mature mouse sciatic nerve bundles, are all Significant increase
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Further research found that the kinase activity of PAK5 is controlled by the upstream kinase AKT.
This signal switches-off SNPH by phosphorylating the mitochondrial anchoring protein Syntaphilin (SNPH), weakening its binding with microtubules.
The anchoring effect of mitochondria promotes the bidirectional transport of mitochondria in axons
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A number of previous studies have found that the transport of mitochondria in axons is significantly abnormal after neurons are acutely injured
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In response to this phenomenon, the study activated the AKT-PAK5 pathway in two different injury models in vitro and found that the transport of mitochondria in the damaged axons of mature neurons was significantly increased, which promoted the transport of healthy mitochondria to the damaged site.
Sufficient ATP maintains local energy supply and guarantees the survival and regeneration of axons after different acute injuries
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More importantly, activation of the PAK5 pathway was found to also play an important role in promoting the regeneration of axons after spinal cord injury in mice
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By activating the AKT-PAK5 signaling pathway, it weakens the binding of the mitochondrial anchoring protein SNPH and microtubules in mature neurons, increases the transport of mitochondria after neuronal axons are damaged, and promotes the transport of healthy mitochondria to the damaged site, thereby accelerating recovery The energy balance of damaged axons promotes the survival and regeneration of damaged axons
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In summary, this study reveals for the first time that the AKT-PAK5-SNPH pathway, as an endogenous signal pathway in mature neuron axons in response to injury stimuli, regulates the transport of mitochondria in axons and maintains the molecular mechanism of energy homeostasis in axons
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Activation of this pathway significantly improves the survival and regeneration of axons after injury, and provides new targets for restoring the energy balance of damaged axons and new clinical treatment ideas for promoting the survival and regeneration of neurons after cerebral ischemia and spinal cord injury
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Sheng Zuhang is the corresponding author of the study, and the first author is Dr.
Huang Ning from Sheng Zuhang's team
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This work is another collaboration between Sheng Zuhang's team and Xu Xiaoming's team in the Department of Neurosurgery of Indiana University School of Medicine following the discovery in 2020 that increasing neuronal energy supply can promote regeneration and functional recovery of spinal cord injury (Han et al.
, Cell Metabolism 2020)
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In recent years, Sheng Zuhang’s research group has systematically studied the transport of mitochondria in neuronal axons and the regulation of energy homeostasis, as well as the relationship between neurodegeneration and neuroregeneration.
A number of related works have been published before (Li et al.
.
, Nature Metabolism 2020; Kang et al.
, Cell 2008; Cai et al.
, Current Biology 2012; Sun & Qiao et al.
, Cell Reports 2013; Chen & Sheng JCB, 2013; Xie & Zhou et al.
, Neuron 2015 ; Zhou et al.
, JCB 2016; Lin & Cheng et al.
, Neuron 2017; Han et al.
, Cell Metabolism 2020) laid a solid foundation for the study of the neuronal acute injury response mechanism
.

Original link: https://doi.
org/10.
1016/j.
cub.
2021.
04.
079 Platemaker: 11 References 1.
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(2020).
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Nature Metabolism 2, 1077-1095.
2.
Qi Han, Yuxiang Xie, Josue D Ordaz, Andrew J Huh, Ning Huang, Wei Wu, Naikui Liu, Kelly A Chamberlain, Zu-Hang Sheng (lead corresponding author), Xiao-Ming Xu (2020).
Recovering energy deficits promotes CNS axonal regeneration and functional restoration after spinal cord injury.
Cell Metabolism 31, 623-641.
3.
Jian-Sheng Kang , Jin-Hua Tian*, Ping-Yue Pan*(*equal), Philip Zald, Cuiling Li, Chuxia Deng, and Zu-Hang Sheng (2008).
Docking of Axonal Mitochondria by Syntaphilin Controls their Mobility and Affects Short-term Facilitation .
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4.
Bing Zhou,Panpan Yu, Mei-Yao Lin, Tao Sun, Yanmin Cheng and Zu-Hang Sheng (2016).
Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits, Journal of Cell Biology, 204, 103-119.
5.
Qian Cai , Hesham Mostafa Zakaria, Anthony Simone, and Zu-Hang Sheng (2012).
Spatial Parkin Translocation and Degradation of Depolarized Mitochondria via Mitophagy in Live Cortical Neurons, Current Biology, 22, 545-552.
6.
Mei-Yao Lin*, Xiu-Tang Cheng* (*co-first author), Prasad Tammineni, Yuxiang Xie, Bing Zhou, Qian Cai, Zu-Hang Sheng (2017).
Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under pathophysiological Conditions.
Neuron, 94, 595- 610.
7.
Yuxiang Xie*, Bing Zhou* (*co-first author), Mei-Yao Lin, Shiwei Wang, Kevin D.
Foust, and Zu-Hang Sheng (2015).
Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice.
Neuron, 87, 355-370.
8.
Tao Sun*, Haifa Qiao* (*co-first author), Ping-Yue Pan, Yanming Chen, and Zu- Hang Sheng (2013).
Mobile axonal mitochondria contribute to the variability of presynaptic strength.
Cell Reports.
9.
Yanmin Chen and Zu-Hang Sheng (2013).
Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport.
Journal of Cell Biology, 202, 351-364.
10.
Natalia S.
Morsci, David H.
Hall, Monica Driscoll, and Zu-Hang Sheng (2016).
Age-related phasic patterns of mitochondrial maintenance in adult C.
elegans neurons.
Journal of Neuroscience, 36, 1373-1385.
(Swipe up and down to read) Reprint instructions [Non-original articles] 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 owns all legal rights.
Offenders must be investigated.
355-370.
8.
Tao Sun*, Haifa Qiao* (*co-first author), Ping-Yue Pan, Yanming Chen, and Zu-Hang Sheng (2013).
Mobile axonal mitochondria contribute to the variability of presynaptic strength.
Cell Reports.
9.
Yanmin Chen and Zu-Hang Sheng (2013).
Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport.
Journal of Cell Biology, 202, 351-364.
10.
Natalia S.
Morsci, David H.
Hall, Monica Driscoll, and Zu-Hang Sheng (2016).
Age-related phasic patterns of mitochondrial maintenance in adult C.
elegans neurons.
Journal of Neuroscience, 36, 1373-1385.
(Swipe up and down to read) Reprint Instructions【 Non-original articles] 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 owns all legal rights.
Offenders must be investigated.
355-370.
8.
Tao Sun*, Haifa Qiao* (*co-first author), Ping-Yue Pan, Yanming Chen, and Zu-Hang Sheng (2013).
Mobile axonal mitochondria contribute to the variability of presynaptic strength.
Cell Reports.
9.
Yanmin Chen and Zu-Hang Sheng (2013).
Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport.
Journal of Cell Biology, 202, 351-364.
10.
Natalia S.
Morsci, David H.
Hall, Monica Driscoll, and Zu-Hang Sheng (2016).
Age-related phasic patterns of mitochondrial maintenance in adult C.
elegans neurons.
Journal of Neuroscience, 36, 1373-1385.
(Swipe up and down to read) Reprint Instructions【 Non-original articles] 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 owns all legal rights.
Offenders must be investigated.
Cell Reports.
9.
Yanmin Chen and Zu-Hang Sheng (2013).
Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport.
Journal of Cell Biology, 202, 351-364.
10.
Natalia S.
Morsci, David H.
Hall, Monica Driscoll, and Zu-Hang Sheng (2016).
Age-related phasic patterns of mitochondrial maintenance in adult C.
elegans neurons.
Journal of Neuroscience, 36, 1373-1385.
(Swipe up and down to read) 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.
Offenders must be investigated.
Cell Reports.
9.
Yanmin Chen and Zu-Hang Sheng (2013).
Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport.
Journal of Cell Biology, 202, 351-364.
10.
Natalia S.
Morsci, David H.
Hall, Monica Driscoll, and Zu-Hang Sheng (2016).
Age-related phasic patterns of mitochondrial maintenance in adult C.
elegans neurons.
Journal of Neuroscience, 36, 1373-1385.
(Swipe up and down to read) 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.
Offenders must be investigated.
1373-1385.
(You can swipe up and down to read) Reprinting instructions [Non-original articles] 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 owns all legal rights.
Offenders must be investigated.
1373-1385.
(You can swipe up and down to read) Reprinting instructions [Non-original articles] 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 owns all legal rights.
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