dictyNews
Electronic Edition
Volume 42, number 8
March 11, 2016

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=========
Abstracts
=========


The inositol-3-phosphate synthase biosynthetic enzyme has 
distinct catalytic and metabolic roles

Anna D. Freja, Jonathan Clarkb, Caroline Le Royc, Sergio Lillad, 
Peter Thomasond, Grant P. Ottoa, Grant Churchill5, Robert Insalld,  
Sandrine P. Clausc, Phillip Hawkinsb, Len Stephensb and 
Robin S.B. Williamsa#

Centre for Biomedical Sciences, School of Biological Sciences, 
Royal Holloway University of London, Egham, Surrey, UK
a; The Babraham Institute, Cambridge, Cambridgeshire, UK
b; Department of Food and Nutritional Sciences, The University of 
Reading, Reading, Berkshire, UK
c. CRUK Beatson Institute for Cancer Research, Glasgow, UK
d. Department of Pharmacology, University of Oxford, Oxford, 
Oxfordshire, UK5


Molecular and Cellular Biology, in press

Inositol levels, maintained by the biosynthetic enzyme inositol-3-
phosphate synthase (Ino1), are altered in a range of disorders 
including bipolar disorder and Alzheimer’s disease. To date, most 
inositol studies have focused on the molecular and cellular effects 
of inositol depletion without considering Ino1 levels. Here we 
employ a simple eukaryote, Dictyostelium, to demonstrate distinct 
effects of loss of Ino1 and inositol depletion. We show that loss 
of Ino1 results in inositol auxotrophy that can only be partially 
rescued by exogenous inositol. Removal of inositol supplementation 
from the ino1- mutant results in a rapid 56% reduction in inositol 
levels, triggering the induction of autophagy, reduced cytokinesis 
and substrate adhesion. Inositol depletion also caused a dramatic 
generalised decrease in phosphoinositide levels that was rescued by 
inositol supplementation. However, loss of Ino1 triggered broad 
metabolic changes consistent with the induction of a catabolic state 
that was not rescued by inositol supplementation. These data suggest 
a metabolic role for Ino1 independent of inositol biosynthesis. To 
characterise this role, an Ino1 binding partner containing SEL1L1 
domains (Q54IX5) was identified with homology to mammalian 
macromolecular complex adaptor proteins. Our findings therefore 
identify a new role for Ino1, independent of inositol biosynthesis, 
with broad effects on cell metabolism.


submitted by: Robin Williams [robin.williams@rhul.ac.uk]
———————————————————————————————————————


Non-Catalytic Roles of Presenilin throughout evolution

Grant P. Otto, Devdutt Sharma and Robin S.B. Williams*

Centre for Biomedical Sciences, School of Biological Sciences, 
Royal Holloway University of London, Egham, TW20 0EX, UK


Journal of Alzheimer's Disease 

Research into Alzheimer’s disease pathology and treatment has 
often focused on presenilin proteins. These proteins provide 
the key catalytic activity of the gamma-secretase complex in 
the cleavage of amyloid precursor protein and resultant amyloid 
tangle deposition. Over the last 25 years, screening novel drugs 
to control this aberrant proteolytic activity has yet to identify 
effective treatments for the disease. In the search for other 
mechanisms of presenilin pathology, several studies have 
demonstrated that mammalian presenilin proteins also act in a 
non-proteolytic role as a scaffold to co-localise key signalling 
proteins. This role is likely to represent an ancestral presenilin 
function, as it has been described in genetically distant species 
including non-mammalian animals, plants and a simple eukaryotic 
amoeba Dictyostelium that diverged from the human lineage over a 
billion years ago. Here, we review the non-catalytic scaffold role 
of presenilin, from mammalian models to other biomedical models, 
and include recent insights using Dictyostelium, to suggest that 
this role may provide an early evolutionary function of presenilin 
proteins.


submitted by: Robin Williams [robin.williams@rhul.ac.uk]
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[End dictyNews, volume 42, number 8]