2016 BDSRA Cooper CLN1, CLN2, CLN3, CLN5, CLN6, CLN7

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!!