dictyNews
Electronic Edition
Volume 39, number 30
October 25, 2013
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Abstracts
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Dictyostelium, a microbial model for brain disease
S.J. Annesley, S. Chen, L.M. Francione, O. Sanislav, A.J. Chavan,
C. Farah, S.W. De Piazza, C.L. Storey, J. Ilievska, S.G. Fernando,
P.K. Smith, S.T. Lay , P.R. Fisher*
Biochimica et Biophysica Acta - General Subjects, in press.
Background
Most neurodegenerative diseases are associated with mitochondrial
dysfunction. In humans mutations in mitochondrial genes result in a
range of phenotypic outcomes which do not correlate well with the
underlying genetic cause. Other neurodegenerative diseases are caused
by mutations that affect the function and trafficking of lysosomes,
endosomes and autophagosomes. Many of the complexities of these
human diseases can be avoided by studying them in the simple
eukaryotic model Dictyostelium discoideum.
Scope of Review
This review describes research using Dictyostelium to study
cytopathological pathways underlying a variety of neurodegenerative
diseases including mitochondrial, lysosomal and vesicle trafficking
disorders.
Major Conclusions
Generalized mitochondrial respiratory deficiencies in Dictyostelium
produce a consistent pattern of defective phenotypes that are caused
by chronic activation of a cellular energy sensor AMPK (AMP-activated
protein kinase) and not ATP deficiency per se. Surprisingly, when
individual subunits of Complex I are knocked out, both AMPK-dependent
and AMPK-independent, subunit-specific phenotypes are observed.
Many nonmitochondrial proteins associated with neurological disorders
have homologues in Dictyostelium and are associated with the function
and trafficking of lysosomes and endosomes. Conversely, some genes
associated with neurodegenerative disorders do not have homologues
in Dictyostelium and this provides a unique avenue for studying these
mutated proteins in the absence of endogeneous protein.
General Significance
Using the Dictyostelium model we have gained insights into the sublethal
cytopathological pathways whose dysregulation contributes to phenotypic
outcomes in neurodegenerative disease. This work is beginning to
distinguish correlation, cause and effect in the complex network of cross
talk between the various organelles involved.
Submitted by Paul Fisher [[log in to unmask]]
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Two Distinct Sensing Pathways Allow Recognition of Klebsiella
pneumoniae by Dictyostelium Amoebae.
Lima WC, Balestrino D, Forestier C, Cosson P.
Cell Microbiol. 2013 Oct 15. [Epub ahead of print]
Recognition of bacteria by metazoans is mediated by receptors that
recognize different types of microorganisms and elicit specific cellular
responses. The soil amoebae Dictyostelium discoideum feeds upon a
variable mixture of environmental bacteria, and it is expected to recognize
and adapt to various food sources. To date, however, no bacteria-sensing
mechanisms have been described. In this study, we isolated a
Dictyostelium mutant (fspA KO) unable to grow in the presence of non-
capsulated Klebsiella pneumoniae bacteria, but growing as efficiently as
wild-type cells in the presence of other bacteria, such as Bacillus subtilis.
FspA KO cells were also unable to respond to K. pneumoniae and more
specifically to bacterially secreted folate in a chemokinetic assay, while
they responded readily to B. subtilis. Remarkably, both WT and fspA KO
cells were able to grow in the presence of capsulated LM21 K. pneumoniae,
and responded to purified capsule, indicating that capsule recognition may
represent an alternative, FspA-independent mechanism for K. pneumoniae
sensing. When LM21 capsule synthesis genes were deleted, growth and
chemokinetic response were lost for fspA KO cells, but not for WT cells.
Altogether, these results indicate that Dictyostelium amoebae use specific
recognition mechanisms to respond to different K. pneumoniae elements.
Submitted by Wanessa de Lima [[log in to unmask]]
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The cyclic AMP phosphodiesterase RegA critically regulates encystation
in social and pathogenic amoebas
Qingyou Du, Christina Schilde, Elin Birgersson, Zhi-hui Chen,
Stuart McElroy and Pauline Schaap
Cellular Signalling, in press
Amoebas survive environmental stress by differentiating into encapsulated
cysts. As cysts pathogenic amoebas resist antibiotic treatment, which
particularly counteracts treatment of vision-destroying Acanthamoeba keratitis.
Limited genetic tractability of amoeba pathogens has left their encystation
mechanisms unexplored. The social amoeba Dictyostelium discoideum forms
spores in multicellular fruiting bodies to survive starvation, while other
dictyostelids, such as Polysphondylium pallidum can additionally encyst as
single cells. Sporulation is induced by cAMP acting on PKA with the cAMP
phosphodiesterase RegA critically regulating cAMP levels. We show here that
RegA is deeply conserved in social and pathogenic amoebas and that deletion
of the RegA gene in P. pallidum causes precocious encystation and prevents
cyst germination. We heterologously expressed and characterized
Acanthamoeba RegA and performed a compound screen to identify RegA
inhibitors. Two effective inhibitors increased cAMP levels and triggered
Acanthamoeba encystation. Our results show that RegA critically regulates
amoebozoan encystation and that components of the cAMP signalling pathway
could be effective targets for therapeutic intervention with encystation.
Submitted by Christina Schilde [[log in to unmask]]
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[End dictyNews, volume 39, number 30]
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