Targeting PTPσ for functional recovery in models of multiple sclerosis

Abstract

Changes in chondroitin sulphate proteoglycans (CSPGs), extracellular matrix proteoglycans, following neural injury lead to the inhibition of neural regeneration and myelin repair. In Multiple Sclerosis (MS), CSPGs are deposited at the border of active and expanding demyelinating lesions and may create a barrier for migration and repopulation by oligodendrocyte progenitor cells (OPCs). CSPG inhibition of axonal regeneration and oligodendrocyte(OL) outgrowth and myelination is mediated, at least in part, by the protein tyrosine phosphatase sigma (PTPσ) receptor, as CSPG binding to PTPσ has been associated with activation of the ROCK pathway and the collapse of growth cones. Identification of PTPσ as a functional receptor for CSPGs in oligodendrocytes provide a therapeutic target by which the deficits associated with demyelinating injury may be limited. Intracellular sigma peptide (ISP) is a newly developed membrane permeable peptide that binds to PTPσ and relieves CSPG-mediated inhibition. Relevant to MS treatment, ISP binding of PTPσ may relieve CSPG presence around demyelinating lesions, leading to OPC access at the lesion sites, making maturation and remyelination permissive. As PTPσ is also highly expressed in oligodendrocyte precursor cells and to a lesser degree in oligodendrocytes, microglia, and astrocytes, I proposed that ISP application could promote remyelination following demyelination while restricting secondary neurodegeneration and neuroinflammation. To test this, I used three animal models most frequently used to mimic the pathology of MS, experimental autoimmune encephalomyelitis (EAE) as an autoimmune model, cuprizone-induced systemic demyelination and lysolecithin (LPC)-injection focal demyelination and investigated functional and histological changes subsequent to ISP treatment. I observed remarkable improvements in behavioural assays coupled with reduced degeneration and demyelination, as well as limited immune infiltration and inflammation in the EAE model. To clarify the cellular effects of modulating PTPσ using ISP, I established primary cell culture models of the main cellular players from the nervous milieu and investigated the effects of their exposure to CSPGs and subsequent application of ISP. I found that all the cell types investigated were inhibited by CSPGs, and this was overcome by PTPσ modulation. Moreover, some characteristic processes such as microglial phagocytosis and OL outgrowth were also restricted in the presence of CSPGs, but this could be reversed by ISP. My study highlights a potential avenue for regeneration in the central nervous system, that, coupled with the available literature, represents a highly advantageous strategy to support regeneration following demyelinating injuries or diseases. To test the signalling pathways involved in ISP-mediated inhibition of PTPσ, I used a chemical compound to target downstream signalling effector ERK and investigated the effects on ISP-induced recovery in the LPC-injection model of focal demyelination. Overall, ISP treatment led to functional recovery and attenuation of pathology in all 3 animal models of MS.