1. Mole Laboratory:
Juvenile Batten Disease
Sara Mole, Michael Bond, Mariana Vieira, Davide Marotta, Sophia kleine Holthaus, Rachel Brown
MRC Laboratory for Molecular Cell Biology, University College London, London, UK, WC1E 6BT, s.mole@ucl.ac.uk
INTRODUCTION and
OBJECTIVES
Ñ Juvenile CLN3 disease, or JNCL, is
caused by a 1 kb deletion within the
CLN3 gene. Other mutations can
affect age of onset, and disease
progression and severity. The exact
function of CLN3 is not known.
Ñ It is important to know what CLN3
does, how it does this, and what
goes wrong in disease, so that new
therapies can be designed.
Ñ Our laboratory is working to
achieve this by simplifying the
system used to answer the
questions or identify new drug
targets or develop therapeutic
approaches, before applying to
more complex human cells and
animal models.
Ñ We are also identifying the
challenges to developing therapy for
CLN3 disease, beginning with the
loss of vision.
KEY PROJECTS WHAT THIS MEANS
FOR THERAPY
Studying the effect of different
mutations in CLN3, first in yeast and
then in human cells
Developing gene therapy for the loss
of vision using mouse models
MIT#
Cell%polarity%
Cell%wall%
Osmoregula=on%
Heat%tolerance% Septa=on%
Vacuolar%%
morphology%/%pH%
wt
wt
Studying what CLN3 does and where it
wt with glucose
does it, in a single cell organism such as
btn1Δ with glucose
yeast (where it is called btn1)
btn1Δ
1 Kb
deletion
Identify new drugs and new targets for therapy in
yeast strains with different CLN3 mutations, using
multiple approaches
Acknowledgements:
Many scientists and families
Vacuole size Cytokinesis delay/septation
Monopolar growth, 7 h 37ºC Cell curving (MT), 4 h 37ºC
THERAPY
1. We are simplifying
learning what CLN3 does
2. We are identifying new
genes or drugs that
rescue CLN3 disease in
yeast
3. We extrapolate these
results to patients cells
and then to fish and
mouse models
4. We use this knowledge
to transfer or design and
then test new and better
therapeutic approaches
5. We use approaches that
work, such as gene
therapy for visual failure
6. We apply this to CLN3
disease
7. We are learning what
challenges need to be
overcome
8. Retaining or restoring
sight will significantly
improve the quality of
life for patients and their
families
RESCUE
Function
Therapy
Mutations
Disease
Genes
Models
Btn1%
Btn1%
Trafficking%
%
Metabolic%
perturba=on%
Golgi%size,%
number,%
shape,%
and%structure%
%
GA#
VAC#
Glucose Glycerol
wt
btn1Δ
wt btn1Δ
Mitochondrial membrane
potential (arbitrary units)
Glucose Glycerol
Glucose Glycerol
Viability (%)
Time (hours)
wt with glycerol
btn1Δ with glycerol
btn1Δ
btn1Δ
200nm
wt
Mutation:
E295K
1kb
deletion
Function/
therapy
targets
cDNA library
Transposon
mutagenesis
Small
molecule/
drug
NCL Resource – A gateway for
Batten disease www.ucl.ac.uk/ncl