Pediatric Storage Disorders Lab(Jon Cooper) New lessons from our work on Batten disease

1. CLN1, CLN2, CLN3,
CLN5, CLN6, CLN7
Pediatric Storage Disorders Lab (Jon Cooper)
New lessons from our work on Batten disease
Jon Cooper (PI), Hemanth Nelvagal, Marta Tarczyluk, Yewande Pearce, Jenny Lange, Charlott Repschlager, Tytus Murphy, Laurent, van Trigt, Ana Assis
Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, jon.cooper@kcl.ac.uk
Los Angeles Biomedical Research Institute,
Department of Pediatrics, Harbor-UCLA Medical Center
David Geffen School of Medicine, University of California, Los Angeles
From 1st August 2016…
The lab is moving to Los Angeles!!
Sorry I can’t be at the BDSRA Family Conference this year,
but I’ll look forward to seeing everyone next year…
This is an exciting opportunity to move the lab’s Batten disease
research forwards more quickly!!
What goes wrong?
ProteinDNA
Function?X
Mutation
X
No Protein Disease
Mistakes or mutations in DNA passed on from one generation to the next means
that proteins that have crucial jobs inside cells don’t get made
There is a failed breakdown & recycling of waste = build up of‘STUFF’
X X X
Where do things happen in the brain? The body is affected too!
It’s not just nerve cells that are important!
Do problems
start in
heart itself?
OR: due to
changes
in the brain?
OR: a faulty
connection
between
them?
PERHAPS a combination of
these events?
Studying this in
mice & human BDHow does this
impact walking?
We normally
think of Batten
disease as mostly
affecting the brain
BUT we now know
(surprisingly)
that the spinal cord
has BIG problems too!
Spinal cord problems start early
before they do in the brain
We see this in ALL sorts of Batten disease
(CLN1, CLN2, CLN3, CLN7 so far…)
We are now looking what happens
in the peripheral nervous system
This happens in people
too (not just mice)…
If we treat the cord directly
we can improve pathology
There are also
problems elsewhere
in the body
+
Brain Body
NOT just a disease
of the brain…
Heart problems
CLN1, CLN3
If we know where and how these
problems occur then we
can try to treat them
How does this happen?
??
CLN3, CLN6, CLN7
Even in the brain
not all parts
are affected the same!
Nerve Cells
Glial Support Cells
Billions…
Up to 50 times more!!
Nerve cells are outnumbered by glial cells that help them
Astrocytes
Microglia
Nerve cells
(neurons)
Grow cells in a dish from Cln1, Cln2 and Cln3 mice
We previously only
thought about nerve cells
BUT all may be affected
by Batten disease
Three way relationship crucial for brain function
What is ‘missing’ is
different in each type of BD
How to ‘fix’ this is likely
to be different too..
How things go wrong is likely
to be different…
Infantile BD (CLN1)
Late infantile BD (CLN2)
Enzyme Deficiency
Also: CLN10/CTSD, CLN5?
CAN move from cell to cell
Juvenile BD (CLN3)
Transmembrane Protein
Also: CLN6, CLN7, CLN8
CAN’T move from cell to cell
(stuck inside cells)
Can they still do their
normal jobs?
If glia are sick then
treating them may help
nerve cells too..
?
Some drug combinations
appear to slow the
disease in Cln3 mice?
CLN1 disease
LOTS of early glial activation, BUT
Glia are sick & harm neurons
CLN3 disease
Glial activation early, but ‘get’s stuck’
Glia are sick (in a different way)
& harm neurons
CLN2 disease
Problems are with nerve cells
and glia are relatively ‘OK’?
What effects do glia
have upon neurons?
Glia are more (or less) important, depending
on the sort of Batten disease
We now have new funding to test
more drugs and find more
effective combinations
How these cells
are affected is
surprisingly
different!!