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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.

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BDSRA 2015 CLN1 Wishart

  • 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.