Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis

Sakamoto, Kazunari; Ozaki, Tomoya; Ko, Yen‐Chun; Tsai, Cheng-Fang; Gong, Yuanhao; Morozumi, Masayoshi; Ishikawa, Yoshimoto; Uchimura, Kenji; Nadanaka, Satomi; Kitagawa, Hiroshi; Zulueta, Medel Manuel L.; Bandaru, Anandaraju; Tamura, Jun’ichi; Hung, Shang‐Cheng

doi:10.1038/s41589-019-0274-x

Cited by 68 publications

(65 citation statements)

References 51 publications

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“…Autophagy is a crucial cellular process in neurons/peripheral nerves after PNI because it (i) removes the degenerated axons allowing for a permissive microenvironment for regeneration [34], (ii) enhances axonal growth and functional recovery after spinal cord injury [35], and (iii) increases sensory and motor axon regeneration [22,36]. Moreover, autophagy flux disruption has been described as sufficient to block axon regeneration [37]. Different ATG proteins have been linked with the regenerative process.…”

Section: Discussionmentioning

confidence: 99%

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

Casas

2020

Cells

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Peripheral nerve injury (PNI) leads to the loss of motor, sensory, and autonomic functions, and often triggers neuropathic pain. During the last years, many efforts have focused on finding new therapies to increase axonal regeneration or to alleviate painful conditions. Still only a few of them have targeted both phenomena. Incipient or aberrant sensory axon regeneration is related to abnormal unpleasant sensations, such as hyperalgesia or allodynia. We recently have discovered NeuroHeal, a combination of two repurposed drugs; Acamprosate and Ribavirin. NeuroHeal is a neuroprotective agent that also enhances motor axon regeneration after PNI. In this work, we investigated its effect on sensory fiber regeneration and PNI-induced painful sensations in a rat model of spare nerve injury and nerve crush. The follow up of the animals showed that NeuroHeal treatment reduced the signs of neuropathic pain in both models. Besides, the treatment favored sensory axon regeneration, as observed in dorsal root ganglion explants. Mechanistically, the effects observed in vivo may improve the resolution of cell-protective autophagy. Additionally, NeuroHeal treatment modulated the P2X4-BDNF-KCC2 axis, which is an essential driver of neuropathic pain. These data open a new therapeutic avenue based on autophagic modulation to foster endogenous regenerative mechanisms and reduce the appearance of neuropathic pain in PNI.

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Section: Discussionmentioning

confidence: 99%

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

Casas

2020

Cells

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“…Chondroitin sulfate E activates PTPRσ, which dephosphorylates cortactin and disrupts autophagy flux at the autophagosome‐lysosome fusion step. Such disruption is required and sufficient for the dystrophic endball formation and inhibition of axonal regeneration (Sakamoto et al, ).…”

Section: Glycosaminoglycans In Axonal Regenerationmentioning

confidence: 99%

“…Such interactions are glycosaminoglycan‐dependent because removing most of the core proteins of the proteoglycans does not affect the development, whereas knocking out glycosaminoglycan modification enzymes in various animal models are detrimental to development (Hayes & Melrose, ; Townley & Bulow, ). Furthermore, specific sulfation patterns in heparan sulfate and chondroitin sulfate are not only responsible for specific biological activities but also for axonal growth or inhibition (Griffith et al, ; Sakamoto et al, ; Shukla, Liu, & Blaiklock, ; Zhang et al, ), which suggest that the patterning information residing in glycosaminoglycans might be crucial for spinal cord regeneration.…”

Section: Introductionmentioning

confidence: 99%

Operation spinal cord regeneration: Patterning information residing in extracellular matrix glycosaminoglycans

Baker-Nigh

Sun

2020

Brain and Behavior

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Introduction Spinal cord injuries are devastating, with many complications beyond paralysis and loss of sensory function. Although spinal cord regeneration can revolutionize treatment for spinal cord injuries, the goal has not yet been achieved. The regenerative mechanism of axolotls demonstrates that the regeneration is a repeat of developmental process that all animals have all the genes, but axolotls have both the genes and the patterning information to do it at the adult stage. Methods A narrative review was conducted. Relevant studies were collected via an English‐language PubMed database search and those known to the authors. Results Research during the past 30 years reveals that growth factors, along with spinal cord extracellular matrix, especially glycosaminoglycans, regulates axonal regrowth. Degrading chondroitin sulfate glycosaminoglycans by injecting the bacterial enzyme chondroitinase improves axonal sprouting and functional recovery after spinal cord injury in both rodents and rhesus monkeys. Furthermore, the brain is one of the first organs to develop during the embryonic period, and heparan sulfate glycosaminoglycans are key molecules required for brain development. Conclusions Patterning information residing in glycosaminoglycans might be key elements in restricting spinal cord regeneration. A recommended solution is not to edit the human genome, considering the conserved signaling pathways between animals, but to take advantage of the regenerative mechanism of axolotls and the current knowledge about the pattern‐forming glycosaminoglycans for successful spinal cord regeneration and clinical applications.

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“…Biochemical analyses revealed that both CS-E and DS as well as heparin, a mimetic of HS, bound to RPTPσ with K d s in the nanomolar range (Katagiri et al, 2018 ). Phosphatase activity is essential for the biological effects of GAG binding to RPTPσ and LAR (Fisher et al, 2011 ; Lee et al, 2016 ), and several proteins, including cortactin, are substrates of RPTPσ (Sakamoto et al, 2019 ). A model was proposed where HS binding to the common GAG-binding site on RPTPσ induced clustering of the extracellular region of RPTPσ, whereas CS binding did not, and the opposing effects of HS and CS GAG chains were attributed to the differential oligomeric state of RPTPσ (Coles et al, 2011 ).…”

mentioning

confidence: 99%

“…More recently, we identified a novel binding site for HS in the juxtamembrane domain on RPTPσ, providing an additional mechanism through which RPTPσ is bifunctional (Katagiri et al, 2018 ; Figure 4 ). Further, a synthetic CS oligosaccharide was found to disrupt autophagy in a sulfation-dependent manner, leading to the inhibition of axonal regeneration (Sakamoto et al, 2019 ). Of particular interest is that presynaptically-expressed LAR and RPTPσ not only bind to GAG chains but also associate with postsynaptic binding partners that are involved in synaptic organization (Takahashi and Craig, 2013 ; Coles et al, 2014 ; Bomkamp et al, 2019 ).…”

mentioning

confidence: 99%

Role of Chondroitin Sulfation Following Spinal Cord Injury

Hussein

Mencio

Katagiri

et al. 2020

Front. Cell. Neurosci.

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Traumatic spinal cord injury produces long-term neurological damage, and presents a significant public health problem with nearly 18,000 new cases per year in the U.S. The injury results in both acute and chronic changes in the spinal cord, ultimately resulting in the production of a glial scar, consisting of multiple cells including fibroblasts, macrophages, microglia, and reactive astrocytes. Within the scar, there is an accumulation of extracellular matrix (ECM) molecules-primarily tenascins and chondroitin sulfate proteoglycans (CSPGs)-which are considered to be inhibitory to axonal regeneration. In this review article, we discuss the role of CSPGs in the injury response, especially how sulfated glycosaminoglycan (GAG) chains act to inhibit plasticity and regeneration. This includes how sulfation of GAG chains influences their biological activity and interactions with potential receptors. Comprehending the role of CSPGs in the inhibitory properties of the glial scar provides critical knowledge in the much-needed production of new therapies.

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Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis

Cited by 68 publications

References 51 publications

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

Operation spinal cord regeneration: Patterning information residing in extracellular matrix glycosaminoglycans

Role of Chondroitin Sulfation Following Spinal Cord Injury

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