dictyNews
Electronic Edition
Volume 39, number 28
October 4, 2013
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Abstracts
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The search for better epilepsy treatments: from slime mould to
coconuts
Matthew C. Walker*1 and Robin S.B. Williams†1
* Department of Clinical and Experimental Epilepsy, Institute of
Neurology, University College London, London WC1N 3BG, U.K.
† Centre for Biomedical Sciences, School of Biological Sciences,
Royal Holloway University of London, Egham TW20 0EX, U.K.
1 joint corresponding authors
Biochemical Society Transactions (Review), In Press
Drug-resistant epilepsy has remained a problem since the inception
of antiepileptic drug development, despite the large variety of
antiepileptic drugs available today. Moreover, the mechanism-of-
action of these drugs is often unknown. This is due to the widespread
screening of compounds through animal models. We have taken a
different approach to antiepileptic drug discovery and have identified
a biochemical pathway in Dictyostelium discoideum (a ‘slime mould’)
that may relate to the mechanism-of-action of valproate, one of the
most commonly used and effective antiepileptic drugs. Through
screening in this pathway, we have been able to identify a whole host
of fatty acids and fatty-acid-derivatives with potential antiepileptic
activity; this was then confirmed in in vitro and in vivo mammalian
seizure models. Some of these compounds are more potent than
valproate and potentially lack many of the major side effects of
valproate (including birth defects and liver toxicity). In addition, one
of the compounds that we have identified is a major constituent of
the ketogenic diet, strongly arguing that it may be the fatty acids and
not the ketogenesis that are mediating the effect of this diet.
Submitted by Robin Williams [[log in to unmask]]
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WASH-driven actin polymerization is required for efficient
mycobacterial phagosome maturation arrest
Margot Kolonko1, Anna Christina Geffken2, Tanja Blumer1,3,
Kristine Hagens2, Ulrich Emil Schaible2 and Monica Hagedorn1
1Bernhard Nocht Institute for Tropical Medicine,
Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany
2Research Center Borstel, Priority Program Infections,
Parkallee 1-40, 23458 Borstel, Germany
3current address: Dept. of Biomedicine, University of Basel,
Hebelstr. 20, 4031 Basel, Switzerland
Cellular Microbiology, in press
Pathogenic mycobacteria survive in phagocytic host cells primarily as
a result of their ability to prevent fusion of their vacuole with lysosomes,
thereby avoiding a bactericidal environment. The molecular mechanisms
to establish and maintain this replication compartment are not well
understood. By combining molecular and microscopical approaches we
show here that after phagocytosis the actin nucleation-promoting factor
WASH associates and generates F-actin on the mycobacterial vacuole.
Disruption of WASH or depolymerization of F-actin leads to the
accumulation of the proton-pumping V-ATPase around the mycobacterial
vacuole, its acidification and reduces the viability of intracellular
mycobacteria. This effect is observed for M. marinum in the model
phagocyte Dictyostelium but also for M. marinum and M. tuberculosis in
mammalian phagocytes. This demonstrates an evolutionarily conserved
mechanism by which pathogenic mycobacteria subvert the actin-
polymerization activity of WASH to prevent phagosome acidification
and maturation, as a prerequisite to generate and maintain a replicative
niche.
Submitted by Monica Hagedorn [[log in to unmask]]
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[End dictyNews, volume 39, number 28]
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