Copaxone interferes with the PrP Sc-GAG interaction.
The hallmark of prion disease-induced neurodegeneration is the accumulation of PrP(Sc), a misfolded form of PrP(C). In addition, several lines of evidence indicate a role for the immune system and, in particular, inflammation in prion disease pathogenesis. In this work, we tested whether Copaxone, an immunomodulatory agent currently used for the treatment of multiple sclerosis, can affect prion disease manifestation in scrapie-infected hamsters. We show here that Copaxone exerted no effect on prion disease incubation time when treatment commenced 2 weeks after i.p. prion infection. However, when Copaxone was mixed with the initial prion inoculum or administered to hamsters weekly starting on the day of infection, prion disease incubation time was prolonged by 30 days. This suggests that Copaxone may affect the initial infection process. In vitro experiments indicate that Copaxone significantly reduced PrP(Sc) binding to both Chinese hamster ovary (CHO) cells and heparin beads and also binds to heparin by itself. Interestingly, Copaxone also abolished PrP(Sc) accumulation in scrapie-infected cells. We propose that Copaxone delays prion infection by competing with the PrP(Sc)-glycosaminoglycans interaction. Whether the immunomodulating activity of Copaxone is related to its heparin binding and anti-prion properties remains to be established.
Engelstein
R
R
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
Ovadia
H
H
Gabizon
R
R
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000068717:Glatiramer Acetate; D006025:Glycosaminoglycans / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D018620:PrPSc Proteins / Q000187:drug effects* / Q000378:metabolism*; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D012608:Scrapie / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
D006025:Glycosaminoglycans; D007155:Immunologic Factors; D008565:Membrane Proteins; D010455:Peptides; D018620:PrPSc Proteins; D000068717:Glatiramer Acetate; D006493:Heparin