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2014 BDSRA Cooper JNCL

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2014 BDSRA Cooper JNCL

  1. 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?