1887

Abstract

Anle138b is an anti-aggregating compound previously shown to delay the onset of scrapie, a transmissible prion disease, although its in vivo efficacy against other prion disease subtypes has not been fully assessed. TgGSS mice that model Gerstmann–Sträussler–Scheinker disease (GSS) via expression of mouse PrP accumulate PrP amyloid plaques in their brains and develop progressive ataxia leading to death in ~160 days. When allowed to feed on food pellets containing anle138b from weaning until death, the brains of TgGSS mice displayed significant reductions in PrP plaque burden, insoluble PrP, and proteinase K-resistant PrP at end stage, compared with TgGSS mice allowed to feed on placebo food pellets. Despite these effects on biological markers of disease, there was no difference in the onset of symptoms or the age at death between the two treatment groups. In contrast, scrapie-inoculated wild-type mice treated with anle138b survived nearly twice as long (254 days) as scrapie-inoculated mice fed placebo (~136 days). They also displayed greater reductions in insoluble and PK-resistant PrP than TgGSS mice. Although these results support an anti-aggregating effect of anle138b, the discordance in clinical efficacy noted between the two prion disease models tested underscores the pathophysiological differences between them and highlights the need to consider differences in susceptibilities among prion subtypes when assessing potential therapies for prion diseases.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001262
2019-05-02
2019-10-22
Loading full text...

Full text loading...

References

  1. Prusiner SB.Prions (les prix nobel lecture) In Frängsmyr T. editor Les Prix Nobel Stockholm, Sweden: Almqvist & Wiksell International; 1998; pp268–323
    [Google Scholar]
  2. Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A 2001;98:9836–9841 [CrossRef]
    [Google Scholar]
  3. Collinge J, Gorham M, Hudson F, Kennedy A, Keogh G et al. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial. Lancet Neurol 2009;8:334–344 [CrossRef]
    [Google Scholar]
  4. Geschwind MD, Kuo AL, Wong KS, Haman A, Devereux G et al. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease. Neurology 2013;81:2015–2023 [CrossRef]
    [Google Scholar]
  5. De Luigi A, Colombo L, Diomede L, Capobianco R, Mangieri M et al. The efficacy of tetracyclines in peripheral and intracerebral prion infection. PLoS One 2008;3:e1888 [CrossRef]
    [Google Scholar]
  6. Forloni G, Iussich S, Awan T, Colombo L, Angeretti N et al. Tetracyclines affect prion infectivity. Proc Natl Acad Sci U S A 2002;99:10849–10854 [CrossRef]
    [Google Scholar]
  7. Haïk S, Marcon G, Mallet A, Tettamanti M, Welaratne A et al. Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13:150–158 [CrossRef]
    [Google Scholar]
  8. Varges D, Manthey H, Heinemann U, Ponto C, Schmitz M et al. Doxycycline in early CJD: a double-blinded randomised phase II and observational study. J Neurol Neurosurg Psychiatry 2017;88:119–125 [CrossRef]
    [Google Scholar]
  9. Forloni G, Tettamanti M, Lucca U, Albanese Y, Quaglio E et al. Preventive study in subjects at risk of fatal familial insomnia: innovative approach to rare diseases. Prion 2015;9:75–79 [CrossRef]
    [Google Scholar]
  10. Bone I, Belton L, Walker AS, Darbyshire J. Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK. Eur J Neurol 2008;15:458–464 [CrossRef]
    [Google Scholar]
  11. Tsuboi Y, Doh-Ura K, Yamada T. Continuous intraventricular infusion of pentosan polysulfate: clinical trial against prion diseases. Neuropathology 2009;29:632–636 [CrossRef]
    [Google Scholar]
  12. Sadowski MJ, Pankiewicz J, Prelli F, Scholtzova H, Spinner DS et al. Anti-PrP Mab 6D11 suppresses PrP(Sc) replication in prion infected myeloid precursor line FDC-P1/22L and in the lymphoreticular system in vivo. Neurobiol Dis 2009;34:267–278 [CrossRef]
    [Google Scholar]
  13. White MD, Mallucci GR. RNAi for the treatment of prion disease: a window for intervention in neurodegeneration? CNS & neurological disorders drug targets. Review 2009;8:342–352
    [Google Scholar]
  14. Moreno JA, Halliday M, Molloy C, Radford H, Verity N et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013;5:206ra138 [CrossRef]
    [Google Scholar]
  15. Cortes CJ, Qin K, Cook J, Solanki A, Mastrianni JA. Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Sträussler-Scheinker disease. J Neurosci 2012;32:12396–12405 [CrossRef]
    [Google Scholar]
  16. Aguib Y, Heiseke A, Gilch S, Riemer C, Baier M et al. Autophagy induction by trehalose counter-acts cellular prion-infection. Autophagy 2009;5:361–369 [CrossRef]
    [Google Scholar]
  17. Polymenidou M, Cleveland DW. Prion-like spread of protein aggregates in neurodegeneration. J Exp Med 2012;209:889–893 [CrossRef]
    [Google Scholar]
  18. Hasegawa M, Nonaka T, Masuda-Suzukake M. Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther 2017;172:22–33 [CrossRef]
    [Google Scholar]
  19. Eraña H, Venegas V, Moreno J, Castilla J. Prion-like disorders and transmissible spongiform encephalopathies: an overview of the mechanistic features that are shared by the various disease-related misfolded proteins. Biochem Biophys Res Commun 2017;483:1125–1136 [CrossRef]
    [Google Scholar]
  20. Woerman AL, Watts JC, Aoyagi A, Giles K, Middleton LT et al. α-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med 2018;8:a024588 [CrossRef]
    [Google Scholar]
  21. Wagner J, Krauss S, Shi S, Ryazanov S, Steffen J et al. Reducing Tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. Acta Neuropathol 2015;130:619–631 [CrossRef]
    [Google Scholar]
  22. Wagner J, Ryazanov S, Leonov A, Levin J, Shi S et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathologica 2013;125:795–813 [CrossRef]
    [Google Scholar]
  23. Brown K, Mastrianni JA. The prion diseases. J Geriatr Psychiatry Neurol 2010;23:277–298 [CrossRef]
    [Google Scholar]
  24. Yang W, Cook J, Rassbach B, Lemus A, DeArmond SJ et al. A new transgenic mouse model of Gerstmann-Straussler-Scheinker syndrome caused by the A117V mutation of PRNP. J Neurosci 2009;29:10072–10080 [CrossRef]
    [Google Scholar]
  25. Martinez Hernandez A, Urbanke H, Gillman AL, Lee J, Ryazanov S et al. The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO Mol Med. 2018;10:32–47 [CrossRef]
    [Google Scholar]
  26. Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D et al. Prion protein conformation in a patient with sporadic fatal insomnia. N Engl J Med 1999;340:1630–1638 [CrossRef]
    [Google Scholar]
  27. Tunnell E, Wollman R, Mallik S, Cortes CJ, DeArmond SJ et al. A novel PRNP-P105S mutation associated with atypical prion disease and a rare PrPSc conformation. Neurology 2008;71:1431–1438 [CrossRef]
    [Google Scholar]
  28. McKinley MP, Bolton DC, Prusiner SB. A protease-resistant protein is a structural component of the scrapie prion. Cell 1983;35:57–62 [CrossRef]
    [Google Scholar]
  29. Asante EA, Linehan JM, Smidak M, Tomlinson A, Grimshaw A et al. Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein. PLoS Pathog 2013;9:e1003643 [CrossRef]
    [Google Scholar]
  30. Pirisinu L, Di Bari MA, D'Agostino C, Marcon S, Riccardi G et al. Gerstmann-Sträussler-Scheinker disease subtypes efficiently transmit in bank voles as genuine prion diseases. Sci Rep 2016;6:20443 [CrossRef]
    [Google Scholar]
  31. Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P et al. A transmembrane form of the prion protein in neurodegenerative disease. Science 1998;279:827–834 [CrossRef]
    [Google Scholar]
  32. Hsiao KK, Scott M, Foster D, Groth DF, DeArmond SJ et al. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 1990;250:1587–1590 [CrossRef]
    [Google Scholar]
  33. Chiesa R, Piccardo P, Ghetti B, Harris DA. Neurological illness in transgenic mice expressing a prion protein with an insertional mutation. Neuron 1998;21:1339–1351 [CrossRef]
    [Google Scholar]
  34. Jackson WS, Borkowski AW, Faas H, Steele AD, King OD et al. Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice. Neuron 2009;63:438–450 [CrossRef]
    [Google Scholar]
  35. Chesebro B, Trifilo M, Race R, Meade-White K, Teng C et al. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 2005;308:1435–1439 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001262
Loading
/content/journal/jgv/10.1099/jgv.0.001262
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error