Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury

Bradley T. Lang; Jared M. Cregg; Marc A. Depaul; Amanda P. Tran; Kui Xu; Scott M. Dyck; Kathryn M. Madalena; Benjamin P. Brown; Yi Lan Weng; Shuxin Li; Soheila Karimi-Abdolrezaee; Sarah A. Busch; Yingjie Shen; Jerry Silver

doi:10.1038/nature13974

Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury

Bradley T. Lang, Jared M. Cregg, Marc A. Depaul, Amanda P. Tran, Kui Xu, Scott M. Dyck, Kathryn M. Madalena, Benjamin P. Brown, Yi Lan Weng, Shuxin Li, Soheila Karimi-Abdolrezaee, Sarah A. Busch, Yingjie Shen, Jerry Silver

Houston Methodist

Research output: Contribution to journal › Article › peer-review

372 Scopus citations

Abstract

Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ(PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.

Original language	English (US)
Pages (from-to)	404-408
Number of pages	5
Journal	Nature
Volume	518
Issue number	7539
DOIs	https://doi.org/10.1038/nature13974
State	Published - Feb 19 2015

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title = "Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury",

abstract = "Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ(PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.",

author = "Lang, {Bradley T.} and Cregg, {Jared M.} and Depaul, {Marc A.} and Tran, {Amanda P.} and Kui Xu and Dyck, {Scott M.} and Madalena, {Kathryn M.} and Brown, {Benjamin P.} and Weng, {Yi Lan} and Shuxin Li and Soheila Karimi-Abdolrezaee and Busch, {Sarah A.} and Yingjie Shen and Jerry Silver",

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AU - Lang, Bradley T.

AU - Cregg, Jared M.

AU - Depaul, Marc A.

AU - Tran, Amanda P.

AU - Xu, Kui

AU - Dyck, Scott M.

AU - Madalena, Kathryn M.

AU - Brown, Benjamin P.

AU - Weng, Yi Lan

AU - Li, Shuxin

AU - Karimi-Abdolrezaee, Soheila

AU - Busch, Sarah A.

AU - Shen, Yingjie

AU - Silver, Jerry

PY - 2015/2/19

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N2 - Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ(PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.

AB - Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ(PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.

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Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury

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