Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion.

Abstract

Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Sträussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrP(res) ) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3-10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP(res) in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP(res) was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain.

• Authors: Hiroyuki Honda, Kensuke Sasaki, Haruhiko Minaki, Kenta Masui, Satoshi O Suzuki, Katsumi Doh-Ura, Toru Iwaki
• Journal: Neuropathology : official journal of the Japanese Society of Neuropathology (Neuropathology) Vol. 32 Issue 2 Pg. 124-32 (Apr 2012) ISSN: 1440-1789 [Electronic] Australia
• PMID: 21801238 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Society of Neuropathology.

Chemical References

• Prions
• Pentosan Sulfuric Polyester
• Peptide Hydrolases

Topics

• Aged
• Creutzfeldt-Jakob Syndrome (drug therapy, enzymology, pathology)
• Female
• Humans
• Infusions, Intraventricular
• Male
• Middle Aged
• Pentosan Sulfuric Polyester (administration & dosage)
• Peptide Hydrolases (metabolism)
• Prion Diseases (drug therapy, enzymology, pathology)
• Prions (metabolism)