Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice

Abstract

The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the early molecular signs demyelination was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.

The prion protein is not required for peripheral nerve de- and remyelination after crush injury

“…GFAP levels in uninjured Prnp ZH3/ZH3 mice appeared higher than in WT mice. By comparing GFAP expression in uninjured Prnp ZH3/ZH3 and WT nerves ( Fig 1e ) we found that Prnp ZH3/ZH3 mice had on average a two-fold higher baseline GFAP level when compared to WT mice (relative increase to WT GFAP level as quantified from Fig 1e : WT 1.00 ± 0.17 ( 6 ); Prnp ZH3/ZH3 2.05 ± 0.09 ( 6 ); mean ± SEM ( n ); p = 0.0003, unpaired t-test), which is in line with our previously published findings [ 31 ].…”

“…We have previously described that Prnp ZH3/ZH3 mice exhibit an early upregulation of repair Schwann cell markers in sciatic nerves, which probably represents an early sign of the peripheral nerve disease [ 31 ]. In the present study, we confirmed that the 2–3 months old Prnp ZH3/ZH3 mice undergoing crush injury showed a two-fold upregulation of GFAP in their uninjured sciatic nerves when compared to WT mice.…”

Glial activation in prion diseases is strictly nonautonomous and requires neuronal PrPSc

“…Surprisingly, no changes in the expression of neuron-enriched transcript were detectable at this time point. Instead, suppression of neuronal transcripts was only observed at the terminal stage of disease (Sorce et al, 2020). The onset of changes associated with actively translating genes during the course of prion infection also revealed glial perturbation as the major contributors in driving the course of prion disease (Scheckel et al, 2020).…”

“…Previous studies have longitudinally mapped transcriptional changes associated with prion disease in mice, and revealed changes in gene expression from as early as 4 weeks post prion infection (Sorce et al, 2020). We asked if GFAP Cre ;loxPrP mice, which do not develop clinical signs after prion infection, exhibit transcriptional changes upon prion infection.…”

“…However, recent molecular studies are painting a starkly different picture. Transcriptomic analysis performed in prion-infected mice over the course of disease have revealed dramatic aberrations of glia-enriched genes coinciding with the onset of clinical signs, whereas neuronal changes were less pronounced and were only detected at the terminal stage of the disease (Sorce et al, 2020). Similarly, a quantitative analysis of mRNA translation during the course of prion diseases has found that almost all changes during the progression of prion disease occur in non-neuronal cells, except very late in disease (Scheckel et al, 2020).…”