This study examines synaptic changes in a mouse model of infantile Batten disease. Researchers isolated synapses from mouse brain regions and identified protein differences between healthy and diseased synapses. They found that synaptic breakdown begins earlier in certain brain regions, suggesting some synapses are more vulnerable than others. The team then used a fruit fly model of Batten disease to test whether modifying levels of candidate proteins identified in mouse synapses could slow disease progression, identifying potential therapeutic targets.

1. Wishart Laboratory :
Infantile Batten Disease – A synaptic Study
Maica Llavero Hurtado1, Tom Gillingwater1, Giusy Pennetta1, Jon Cooper2 & Tom Wishart1
1 University of Edinburgh, 2 Kings College London, United Kingdom. Contact: T.M.Wishart@ed.ac.uk (Neurobiology Division, The Roslin Institute, University of Edinburgh)
Informational Text Here
Acknowledgements: Dundee Proteomics Facility, Members of the Pennetta, Cooper and Wishart labs.
Maica Llavero is funded by the Darwin Trust, Tom Wishart is funded by the BBSRC and MRC.
1. What is the problem?
DNA
muta)on
Non-­‐func)onal
CLN1
protein
Neuron
degenera)on
2. Why are synapses
important?
…a
cell
body
…an
axon
…and
synapses
A
neuron
has…
5. Identification of protein differences in synapses
B
Thalamus
&
Cortex
dissec:on
Isola:on
of
synapses
A
1 month 3 month 5 month 7 month
Late-symptomaticEarly-symptomatic
Disease
onset?
controls
controls
controls
controls
cln1/-­‐
cln1-­‐/-­‐
cln1-­‐/-­‐
cln1-­‐/-­‐
Protein
extrac:on
C
Protein
iden:fica:on
and
quan:fica:on
D
Protein
A
Protein
B
6. Identification of disease regulators in other animal models
Healthy
eye
Healthy
Fruit
Fly
BaGen
Disease
Fruit
Fly
Small
and
degenera:ve
eye
Healthy
synapse
Disrupted
synapse
Protein
A
Protein
B
We
can
modify
the
levels
of
our
protein
candidates
(iden:fied
in
5)
in
a
fly
model
of
BaGen
Disease
to
see
if
we
can
change
disease
progression.
Modifying
Protein
A
levels
we
make
the
eye
bigger.
Makes
disease
beGer.
Modifying
Protein
B
levels
we
make
the
eye
smaller.
Makes
disease
worse.
7. What does this means
for therapy?
Biochemistry
techniques
Small
animal
models
Large
animal
models
Human
Can
we
target
our
candidates
with
drugs?
Can
these
drugs
become
a
therapy
for
neurodegenera:on?
The brain is a very complex organ. It contains
billions of cells called neurons. Neurons form a
very tight network of connections. When this
network is disrupted it can cause a wide range
of different diseases.
In Batten disease, synapses (communication
points between nerve cells/neurons) begin to
break down early in disease progression. The
reasons why synapses are so vulnerable is
unknown.
Our laboratory is trying to work out what
mechanisms govern the vulnerability of
synapses and could therefore be important in
regulating disease progression.
Neurons appear to be quite complicated
cells. There are many types of neurons but
they all have synapses. Synapses are
e s s e n t i a l c o n n e c t i o n s e n a b l i n g
communication between neurons. Their
stability is essential for normal brain
function.
Synapses break down at very early disease
stages in many neurodegenerative
conditions including Alzheimer’s,
Huntington’s, Motor Neuron and Batten
diseases. It is therefore imperative to
understand the role of synapses in disease.
4. What happens in
disease?
1 month 12 month 3 years 10 years
Late-symptomaticEarly-symptomatic
Disease
onset?
• re:nal
degenera:on
• blindness
• cogni:ve
and
motor
deficits
• seizures
• flat
EEG
• Premature
mortality
1 month 3 month 5 month 7 month
Late-symptomaticEarly-symptomatic
Disease
onset?
synap:c
breakdown
beginning
in
thalamus
• Seizures
• Death
Mouse
Model
Human
synap:c
breakdown
beginning
in
cortex
Mouse
brain
The brain can be subdivided into different areas
by the cell types contained within and functions
performed by that portion of the brain.
Not all brain regions are affected at the same time
in neurodegenerative disease. For example, in
Alzheimer’s hippocampus goes first. In
Huntington’s it is striatum. This is also true for
Batten Disease. In the mouse models available
for the disease, synaptic breakdown is first
detected in thalamus and then later in cortex.
This raises the question: what makes some
synapses more vulnerable than others?
CLN1
3. What is CLN1 doing in
the synapse?
CLN1 protein is not specific to neurons. It is involved
in the function of lysosomes which are part of the
machinery for waste clearance present in every cell.
If lysosomes and therefore CLN1 are present in all
cell types why does its loss have such a profound
effect on neurons, presenting as a neurodegenerative
disease?
The presence of CLN1 protein must therefore have
different consequences in different tissues and be
particularly important for the maintenance of
neurons. We therefore need to know what CLN1
interacts with in neurons and their synapses.
We use what is known about synaptic breakdown in CLN1 mouse models to
examine how the composition of synapses changes due to the loss of CLN1 and
throughout disease progression. We need protein extractions from mouse brain,
specialised equipment, powerful computers and complex software to create and
analyze the data.
This workflow allows us to infer what CLN1 interacts with in synapses (see 3
above), to identify proteins which could control the stability of synapses (see 4
above) and regulate disease progression (see 6 next).
E
Correla:on
We can model Batten disease in flies. Flies also have synapses which break down with Batten like mutations. However, their most obvious
effect are alterations in the eye. Whilst they are obviously not as complex as humans, they are useful for testing candidates for their
potential in therapy. After identifying interesting protein candidates we target them in our Batten disease flies. By modifying the levels of
our protein candidates (identified in 5) we see if they can make the Batten disease eye fly better. We can successfully identify proteins
changed in synapses due to loss of CLN1 which can change the disease in Batten flies.
These results are extremely preliminary and
testing of candidates is needed in more
“biologically relevant” larger models before we
can be sure they well be useful for humans.
However, these findings are an important proof of
principle because it means that by starting with
what is happening in synapses we can now
search for candidates which change the rate of
degeneration in Batten.
It also means that successful candidates may also
be effective in a range of neurodegenerative
diseases where synapse are early pathological
targets.
We are here
Some of the generic schematics presented here are modified from the internet.