Neurodegenerative Diseases & Neural Repair - The Strittmatter Lab at Yale School of Medicine

Transcript

• 00:06The brain is a connection of neurons.
• 00:09Each neuron has to talk to one another.
• 00:11They extend over long distances, but at their very tip,
• 00:16they release a chemical onto a second neuron, which then creates a network.
• 00:21If you don't have synapses, the neurons might be there,
• 00:24but they can't talk to one another.
• 00:25You don't have a neural network and you can't carry out any cognitive functions.
• 00:30Unfortunately, what happens in a lot of these different neurodegenerative diseases
• 00:34they start losing synapses
• 00:36and whatever part of the brain is affected,
• 00:39it's normal job is lost.
• 00:42In Alzheimer's, It's quite widespread
• 00:45but of course most affects the memory areas of the brain.
• 00:48Whereas in Parkinson's disease, this may be more in the motor circuits
• 00:53and that's why people have more trouble moving
• 00:56rather than trouble with cognition in most cases.
• 01:05In these different diseases, certain proteins start piling up in excess in big aggregates,
• 01:12clumps in the brain.
• 01:13Each neurodegenerative disease, there's a different protein piling up.
• 01:18Somehow these protein aggregates cause the synapse loss.
• 01:22So what we're interested in is what is the biochemical, cellular, molecular basis
• 01:30for these protein aggregates damaging the synapses.
• 01:33We've worked hard to figure out a way to target those proteins with drugs.
• 01:39The striking thing is, if we can stop this damage,
• 01:42how can we get recovery of function?
• 01:45So we've also had a long standing interest in how to repair
• 01:49connections in the brain.
• 01:59We want to model things that are based on human cells and human disease.
• 02:04So a key thing that we do is culture human neurons
• 02:10from induced pluripotent stem cells.
• 02:12So we have human neurons in a dish
• 02:16and then we can extract the misfolded
• 02:20amyloid beta protein from a human autopsy
• 02:24and add it to those neurons and demonstrate that it causes synapse loss there.
• 02:29And again, these drugs we test in a human cell model.
• 02:33That's entering clinical trials.
• 02:35Our hope is that it stops the disease process,
• 02:38that is the loss of synapses actually restores memory function.
• 02:43In terms of understanding how these drugs work at a detailed level,
• 02:48even at atomic resolution,
• 02:51we use a number of techniques like cryo-electron microscopy
• 02:56which allows us to actually look
• 02:58beyond the limits of light microscopy, to see the actual atomic structure
• 03:03of these receptor proteins and how the drug binds to them.
• 03:08Another key tool that we use
• 03:11is based on what's called transcriptomics,
• 03:16which allows us to look at all the genes that are expressed
• 03:19in all the different cells in the brain.
• 03:22When we expose them to amyloid beta or other aggregated proteins,
• 03:27we could ask, how do all the genes go up or down
• 03:31in different cell types in the brain and understand what the entire
• 03:36sort of genomic response to this pathology is,
• 03:39and the extent to which the drug will reverse
• 03:43some or all of those gene expression changes.
• 03:52We’d like to sort out the different mechanisms
• 03:56for different neurodegenerative diseases and how we can intervene.
• 04:02We touch on a lot of different things from very basic molecular stuff
• 04:06to cellular stuff and then importantly to clinical applications,
• 04:10and I think a real benefit at Yale
• 04:14is the way it's so easy to collaborate here
• 04:17across disciplines, across laboratories,
• 04:21especially from laboratory basic science
• 04:25to clinical scientists and clinical trials.
• 04:28Sort of the collaboration and cross-disciplinary
• 04:33research at Yale is absolutely essential
• 04:36for this type of research, and it's very easy to achieve at Yale.