Simon W F Mok

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

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Publications (6)16.79 Total impact

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    ABSTRACT: Prion diseases have a significant inflammatory component. Glia activation, which is associated with increased production of cytokines and chemokines, may play an important role in disease development. Among the chemokines upregulated highly and early upregulated during scrapie infections are ligands of CXCR3. To gain more insight into the role of CXCR3 in a prion model, CXCR3-deficient (CXCR3(-/-)) mice were infected intracerebrally with scrapie strain 139A and characterized in comparison to similarly infected wild-type controls. CXCR3(-/-) mice showed significantly prolonged survival times of up to 30 days on average. Surprisingly, however, they displayed accelerated accumulation of misfolded proteinase K-resistant prion protein PrP(Sc) and 20 times higher infectious prion titers than wild-type mice at the asymptomatic stage of the disease, indicating that these PrP isoforms may not be critical determinants of survival times. As demonstrated by immunohistochemistry, Western blotting, and gene expression analysis, CXCR3-deficient animals develop an excessive astrocytosis. However, microglia activation is reduced. Quantitative analysis of gliosis-associated gene expression alterations demonstrated reduced mRNA levels for a number of proinflammatory factors in CXCR3(-/-) compared to wild-type mice, indicating a weaker inflammatory response in the knockout mice. Taken together, this murine prion model identifies CXCR3 as disease-modifying host factor and indicates that inflammatory glial responses may act in concert with PrP(Sc) in disease development. Moreover, the results indicate that targeting CXCR3 for treatment of prion infections could prolong survival times, but the results also raise the concern that impairment of microglial migration by ablation or inhibition of CXCR3 could result in increased accumulation of misfolded PrP(Sc).
    Journal of Virology 11/2008; 82(24):12464-71. · 5.08 Impact Factor
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    ABSTRACT: Prion diseases are fatal and at present there are neither cures nor therapies available to delay disease onset or progression in humans. Inspired in part by therapeutic approaches in the fields of Alzheimer's disease and amyotrophic lateral sclerosis, we tested five different drugs, which are known to efficiently pass through the blood-brain barrier, in a murine prion model. Groups of intracerebrally prion-challenged mice were treated with the drugs curcumin, dapsone, ibuprofen, memantine and minocycline. Treatment with antibiotics dapsone and minocycline had no therapeutic benefit. Ibuprofen-treated mice showed severe adverse effects, which prevented assessment of therapeutic efficacy. Mice treated with low- but not high-dose curcumin and mice treated with memantine survived infections significantly longer than untreated controls (P<0.01). These results encourage further research efforts to improve the therapeutic effect of these drugs.
    Journal of General Virology 02/2008; 89(Pt 2):594-7. · 3.13 Impact Factor
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    ABSTRACT: Galectin-3 is a multi-functional protein and participates in mediating inflammatory reactions. The pronounced overexpression of galectin-3 in prion-infected brain tissue prompted us to study the role of this protein in a murine prion model. Immunofluorescence double-labelling identified microglia as the major cell type expressing galectin-3. Ablation of galectin-3 did not affect PrP(Sc)-deposition and development of gliosis. However, galectin-3(-/-)-mice showed prolonged survival times upon intracerebral and peripheral scrapie infections. Moreover, protein levels of the lysosomal activation marker LAMP-2 were markedly reduced in prion-infected galectin-3(-/-)-mice suggesting a role of galectin-3 in regulation of lysosomal functions. Lower mRNA levels of Beclin-1 and Atg5 in prion-infected wild-type and galectin-3(-/-)-mice indicated an impairment of autophagy although autophagosome formation was unchanged. The results point towards a detrimental role of galectin-3 in prion infections of the CNS and suggest that endo-/lysosomal dysfunction in combination with reduced autophagy may contribute to disease development.
    Biochemical and Biophysical Research Communications 09/2007; 359(3):672-8. · 2.28 Impact Factor
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    ABSTRACT: Prion diseases are fatal and at present there are neither cures nor palliative therapies known/available, which delay disease onset or progression. Cholesterol-lowering drugs have been reported to inhibit prion replication in infected cell cultures and to modulate inflammatory reactions. We aimed to determine whether simvastatin-treatment could delay disease onset in a murine prion model. Groups of mice were intracerebrally infected with two doses of scrapie strain 139A. Simvastatin-treatment commenced 100 days postinfection. The treatment did not affect deposition of misfolded prion protein PrP(res). However, expression of marker proteins for glia activation like major histocompatibility class II and galectin-3 was found to be affected. Analysis of brain cholesterol synthesis and metabolism revealed a mild reduction in cholesterol precursor levels, whereas levels of cholesterol and cholesterol metabolites were unchanged. Simvastatin-treatment significantly delayed disease progression and prolonged survival times in established prion infection of the CNS (p < or = 0.0003). The results suggest that modulation of glial responses and the therapeutic benefit observed in our murine prion model of simvastatin is not due to the cholesterol-lowering effect of this drug.
    Biochemical and Biophysical Research Communications 10/2006; 348(2):697-702. · 2.28 Impact Factor
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    ABSTRACT: Disinfectants containing 3-methyl-4-chlorophenol were tested for their capacity to inactivate the infectious agent of scrapie. Coincubation of brain homogenates prepared from terminally ill scrapie-infected hamsters with the disinfectants rendered the prion protein PrP(Sc) sensitive to proteinase K digestion. Inoculation of hamsters with disinfectant-treated samples indicated a reduction in infectivity levels to below the limit of detection.
    Infection Control and Hospital Epidemiology 08/2006; 27(7):778-80. · 4.02 Impact Factor

Publication Stats

99 Citations
16.79 Total Impact Points


  • 2008
    • Charité Universitätsmedizin Berlin
      • Institute of Neuropathology
      Berlín, Berlin, Germany
  • 2006–2008
    • Robert Koch Institut
      • Project 23: Neurodegenerative Diseases
      Berlín, Berlin, Germany