Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury
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Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. / Lang, Bradley T; Cregg, Jared M; DePaul, Marc A; Tran, Amanda P; Xu, Kui; Dyck, Scott M; Madalena, Kathryn M; Brown, Benjamin P; Weng, Yi-Lan; Li, Shuxin; Karimi-Abdolrezaee, Soheila; Busch, Sarah A; Shen, Yingjie; Silver, Jerry.
In: Nature, Vol. 518, No. 7539, 19.02.2015, p. 404-408.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury
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
Y1 - 2015/2/19
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.
KW - Amino Acid Sequence
KW - Animals
KW - Chondroitin Sulfate Proteoglycans/metabolism
KW - Extracellular Matrix/chemistry
KW - Female
KW - Growth Cones/drug effects
KW - Humans
KW - Mice
KW - Molecular Sequence Data
KW - Nerve Regeneration/drug effects
KW - Protein Binding/drug effects
KW - Rats
KW - Rats, Sprague-Dawley
KW - Receptor-Like Protein Tyrosine Phosphatases, Class 2/antagonists & inhibitors
KW - Spinal Cord Injuries/metabolism
U2 - 10.1038/nature13974
DO - 10.1038/nature13974
M3 - Journal article
C2 - 25470046
VL - 518
SP - 404
EP - 408
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7539
ER -
ID: 248114226