1. Pediatric Storage Disorders Laboratory (Jon Cooper):
Juvenile Batten Disease
Jon Cooper (PI), Brenda Williams (co-PI), Greg Anderson, Marta Tarczyluk, Yewande Pearse, Neuroscience, Institute of Psychiatry, King’s College London, jon.cooper@kcl.ac.uk
KEY PROJECTS
X
MANY effects
of disease
Can we block them?
What do we do in the lab?
From brains…. …. to data
Looking closely
at cells
Human BD
Studying animal models that have BD
‘Knockout’ mice
Genetic models to study
what happens, when?
Large Animals
Bigger brains that
are more like
humans
Cutting sections Cells in a dish
Measuring
and counting
Problems with glia in the Juvenile BD brain?
Astrocytes Microglia
WT Juvenile WT Juvenile
Unstimulated
Stimulated Juvenile BD glial don’t respond like they should
Juvenile BD glia aren’t
very good at releasing
chemicals that they
should do
Is this a problem
for brain cells?
WT Glia
WT Neurons
DAPI LIVE/DEAD Dye
MAP2
DAPI LIVE/DEAD Dye
MAP2
Juvenile Glia
DAPI LIVE/DEAD Dye
MAP2
Juvenile Neurons
DAPI LIVE/DEAD Dye
MAP2
Juvenile BD glia harm
brain cells
&
Healthy glia can
rescue sick brain cells
What happens in the Juvenile BD brain?
Activation of the
support cells (Glia)
needed for nerve
cells to work
properly
Astrocytosis
Problems with
cell-cell
communication
Synapses
‘go wrong’
Activation of brain’s
immune system
Microgliosis Entry of immune
cells from the blood
Lymphocyte
Infiltration Loss of Brain Cells
DISEASE PROGRESSION
Infiltration by the body’s
immune system
Auto-immunity
Which of these is
most important?
Can we block these?
What’s the problem
?Mutations in the CLN3 gene
CLN3
1Kb (major) deletion
& other mutations
Altered CLN3
Protein
CLN3 protein is
‘locked’, in cell walls
Function of CLN3
still unknown
How are different cell types
affected in Juvenile BD?
Brain Support Cells
(Astrocytes)
Brain Immune Cells
(Microglia)
Brain Cells
(Neurons)
All cells have the
same mutation
Can they still do
their normal jobs?
Which is the
most ‘important’?
Which
interaction(s)
goes wrong?
Which can
we treat?
X
What does this
mean for therapy?
The juvenile BD brain is attacked
by the body’s immune system
Blocking this ‘autoimmune response’
with CellCept improves the disease
(with the Pearce Lab)
Testing if treating brain inflammation
will be any better (or help more)…
?
Testing anti-inflammatory drugs in mice
Some combinations may help more
Is this a problem in the living brain too?
Mice which have juvenile BD just in glia: what happens?
(with the Weimer, Pearce and Kielian Labs)
Making a human BD model in a dish
to screen for new drugs
‘Genome editing’
using ‘molecular scissors’
allows us to put the Batten
disease-causing mutation
into human cells
This will give us a human juvenile BD model
for drug screening
Effects in the
body too?