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Modulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis

Fucheng Luo1, Amanda Phuong Tran2, Li Xin1

  • 1Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.

Nature Communications
|October 10, 2018
PubMed

Insights

Inhibiting chondroitin sulfate proteoglycans (CSPGs) and protein tyrosine phosphatase sigma (PTPσ) signaling with Intracellular Sigma Peptide (ISP) promotes myelin repair and functional recovery in animal models of Multiple Sclerosis (MS). This approach aids oligodendrocyte progenitor cell (OPC) migration and maturation.

Area of Science:

  • Neuroscience
  • Immunology
  • Regenerative Medicine

Background:

  • Multiple Sclerosis (MS) involves central nervous system (CNS) inflammation, oligodendrocyte (OL) death, and demyelination, leading to functional deficits.
  • Increased inhibitory chondroitin sulfate proteoglycans (CSPGs) in MS lesions impede myelin regeneration.
  • CSPGs exert their inhibitory effects by binding to their receptor, protein tyrosine phosphatase sigma (PTPσ), on oligodendrocyte progenitor cells (OPCs).

Purpose of the Study:

  • To investigate the role of CSPG/PTPσ signaling in failed remyelination in MS.
  • To evaluate the therapeutic potential of inhibiting CSPG/PTPσ interactions for promoting myelin repair in MS models.

Main Methods:

  • Utilized animal models of MS.
  • Administered systemically deliverable Intracellular Sigma Peptide (ISP) to inhibit CSPG/PTPσ signaling.
  • Assessed OPC migration, maturation, and remyelination.
  • Analyzed downstream molecular targets, including matrix metalloproteinase-2 (MMP-2).

Main Results:

  • Inhibition of CSPG/PTPσ signaling by ISP significantly promoted OPC migration, maturation, and remyelination in MS models.
  • ISP treatment led to functional recovery in animal models of MS.
  • PTPσ modulation resulted in the upregulation of MMP-2, facilitating CSPG digestion by OPCs.

Conclusions:

  • CSPG/PTPσ interactions critically inhibit OPCs and impede remyelination in MS.
  • Targeting CSPG/PTPσ signaling with ISP represents a promising therapeutic strategy for promoting myelin repair and functional recovery in MS.

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