dictyNews
Electronic Edition
Volume 45, number 30
November 22, 2019
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Abstracts
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The contribution of multicellular model organisms to neuronal ceroid
lipofuscinosis research
Robert J. Huber1, Stephanie M. Hughes2, Wenfei Liu3, Alan Morgan4,
Richard I. Tuxworth5, Claire Russell6
1 Department of Biology, Trent University, Peterborough, Ontario, Canada
2 Department of Biochemistry, School of Biomedical Sciences, Brain Health
Research Centre and Genetics Otago, University of Otago, Dunedin, New Zealand
3 School of Pharmacy, University College London, London, UK
4 Department of Cellular and Molecular Physiology, Institute of Translational
Medicine, University of Liverpool, Crown St., Liverpool, UK.
5 Institute of Cancer and Genomic Sciences, University of Birmingham,
Birmingham, UK
6 Department of Comparative Biomedical Sciences, Royal Veterinary College,
Royal College Street, London, UK
BBA Molecular Basis of Disease, accepted
The NCLs (neuronal ceroid lipofuscinosis) are forms of neurodegenerative
disease that affect people of all ages and ethnicities but are most prevalent
in children. Commonly known as Batten disease, this debilitating neurological
disorder is comprised of 13 different subtypes that are categorized based on
the particular gene that is mutated (CLN1-8, CLN10-14). The pathological
mechanisms underlying the NCLs are not well understood due to our poor
understanding of the functions of NCL proteins. Only one specific treatment
(enzyme replacement therapy) is approved, which is for the treating the brain
in CLN2 disease. Hence there remains a desperate need for further research
into disease-modifying treatments. In this review, we present and evaluate the
genes, proteins and studies performed in the social amoeba, nematode, fruit fly,
zebrafish, mouse and large animals pertinent to NCL. In particular, we highlight
the use of multicellular model organisms to study NCL protein function, pathology
and pathomechanisms. Their use in testing novel therapeutic approaches is also
presented. With this information, we highlight how future research in these
systems may be able to provide new insight into NCL protein functions in
human cells and aid in the development of new therapies.
submitted by: Robert Huber [[log in to unmask]]
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MAPK regulation of the phosphodiesterase RegA in early Dictyostelium
development
Nirakar Adhikari, Nick A. Kuburich, and Jeffrey A. Hadwiger
Department of Microbiology and Molecular Genetics, Oklahoma State University
Microbiology 2019 Nov. 15
MAP kinase (MAPK) regulation of cAMP-specific phosphodiesterase function has
been demonstrated in mammalian cells and suspected to occur in other eukaryotes.
Epistasis analysis in the soil amoeba Dictyostelium discoideum suggests the atypical
MAPK Erk2 down regulates the function of the cAMP-specific phosphodiesterase
RegA to regulate the progression of the developmental life cycle. A putative MAPK
docking motif located near a predicted MAPK phosphorylation site was characterized
for contributions to RegA function and binding to Erk2 because a similar docking motif
has been previously characterized in the mammalian PDE4D phosphodiesterase. The
overexpression of RegA with alterations to this docking motif (RegAD-) restored RegA
function to regA- cells based on developmental phenotypes but low levels expression
of RegAD- from the endogenous regA promoter failed to rescue wild-type
morphogenesis. Co-immunoprecipitation analysis indicated that Erk2 associates with
both RegA and RegAD- suggesting the docking motif is not required for this association.
Epistasis analysis between regA and the only other Dictyostelium MAPK, erk1, suggests
Erk1 and RegA can function in different pathways but that some erk1- phenotypes may
require cAMP signaling. These results imply that MAPK down regulation of RegA in
Dictyostelium is accomplished through a different mechanism than MAPK regulation of
cAMP-specific phosphodiesterases in mammalian cells and that the regulation in
Dictyostelium does not require a proximal MAPK docking motif.
submitted by: Jeff Hadwiger [[log in to unmask]]
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Calmodulin-mediated events during the life cycle of the amoebozoan
Dictyostelium discoideum
Danton H. O’Day, Sabateeshan Mathavarajah, Michael A. Myre and Robert J. Huber
Biological Reviews, in press (open access)
This review focusses on the functions of intracellular and extracellular calmodulin,
its target proteins and their binding proteins during the asexual life cycle of
Dictyostelium discoideum. Calmodulin is a primary regulatory protein of calcium
signal transduction that functions throughout all stages. During growth, it mediates
autophagy, the cell cycle, folic acid chemotaxis, phagocytosis, and other functions.
During mitosis, specific calmodulin-binding proteins translocate to alternative
locations. Translocation of at least one cell adhesion protein is calmodulin dependent.
When starved, cells undergo calmodulin-dependent chemotaxis to cyclic AMP
generating a multicellular pseudoplasmodium. Calmodulin-dependent signalling
within the slug sets up a defined pattern and polarity that sets the stage for the final
events of morphogenesis and cell differentiation. Transected slugs undergo
calmodulin-dependent transdifferentiation to re-establish the disrupted pattern and
polarity. Calmodulin function is critical for stalk cell differentiation but also functions
in spore formation, events that begin in the pseudoplasmodium. The asexual life
cycle restarts with the calmodulin-dependent germination of spores. Specific
calmodulin-binding proteins as well as some of their binding partners have been
linked to each of these events. The functions of extracellular calmodulin during growth
and development are also discussed. This overview brings to the forefront the central
role of calmodulin, working through its numerous binding proteins, as a primary
downstream regulator of the critical calcium signalling pathways that have been well
established in this model eukaryote. This is the first time the function of calmodulin
and its target proteins have been documented through the complete life cycle of
any eukaryote.
Submitted by: Danton H. O’Day [[log in to unmask]]
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[End dictyNews, volume 45, number 30]
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