Probing Parkinson's

Parkinson’s is a highly prevalent disorder, most famously now affecting Michael J. Fox. It is known to have a biological cause, this dying off of the dopamine nerve cells. We can treat it by giving patients L-Dopa to replace some of the lacking chemical messenger dopamine and alleviating some of the symptoms.  But in the main, this only helps mask the symptoms for short amount of time. Researchers are hoping to improve available treatments by coming up with clever new techniques to gain a much better understanding of the disorder.  I visited Oxford to find out more....

Richard -   My name is Richard Wade-Martins.  I'm a Lecturer here at the University of Oxford and I also head the recently formed Oxford Parkinson's Disease Centre. 

The critical thing that we really don’t understand about Parkinson's is, of all the billions of neurons that are present in your brain, why is it those that make dopamine that die off?  It’s one of the major unanswered questions in the disease and one of the things we’re focusing here in my laboratory. 

What we’re able to do now for the first time is make neurons in the laboratory from patients and from controls.  Now how do we do that?  You can't drill a hole in somebody’s head and take out some neurons to grow in the dish.  People want to keep hold of their neurons.  They're too precious.  So, what we can do instead is to use new technologies of stem cells. 

So, what we’ve been able to do in the centre is to take a skin biopsy from an individual, either a Parkinson's patient or a control, take that skin biopsy using a hole punch that’s about the same size as a hole you might punch out in a piece of A4 paper.  So you take that skin punch, take that back to the laboratory, chop it up into little bits and those bits of skin fall down to the bottom of your dish and you put a growth medium on top of there, a sort of liquid that contains all these things that cells need to be happy and grow.  And a type of cell called a fibroblast will start to grow out from the skin culture.  So after about 2 or 3 weeks, the cells have grown out from your skin sample and you now have a culture of growing cells from either patient or a control. 

What you then do is you can use various genetic tricks if you like.  You can add to these fibroblasts a number of different cellular reprograming factor as we call them – that are able to turn back the clock if you like, on these fibroblasts.  You're able to genetically persuade the fibroblasts they're not skin cells anymore, but they're stem cells.  And these cells will now grow in your dish as stem cells.  They're called induced pluripotent stem cells.  They're induced because you’ve turned them into stem cells and they're pluripotent.  They will go on to become any cell type you like. 

So, once you’ve got stem cells from your patients, you can now turn them into a cell type that you wish to study.  So, if we’re in interested for example in cardiovascular disease, we’d turn them into cells of the heart and study that.  So, what we do in the lab, we’re interested in dopamine neurons, how they work, and how they die so we turn these stem cells into dopamine neurons.

Hannah -   So, this exciting new technology of turning skin cells into dopamine nerve cells provides a method by which to investigate how the cells of patients with Parkinson's differ to other people’s and why they're more susceptible to dying in the first place.  The idea being, that once you understand how these cells die in the dish, you can first of all screen for new molecules that may help them survive and put us on the road to developing, for the first time, therapies in Parkinson's that can stop the cells dying rather than just supplement the dopamine that’s already lost.  Richard explains how they're using this technique in the lab to do this.

Richard -   So, the dopamine neurons in an individual and even the patient will work quite happily for 30, 40 or 50 years and then they’ll start dying.  My PhD students and Postdocs don’t want to work in the lab growing these neurons for 50 years, so we have to try and understand what might be changing much earlier. 

So, when dopamine neurons die in a patient, they accumulate aggregates, ‘gluggy’ bits of proteins if you like, called Lewy bodies and these Lewy bodies form as the neurons die over decades.  We’re not working on that timescale, so we have to better understand what are the very earliest changes that may occur in these neurons to give us the first clue as to how they're starting to function differently.  And we’re starting to understand and investigate aspects of neuron biology that may be different in patients rather the controls. 

So, there's various things we could study.  We can study how they make dopamine, how they release dopamine.  We can study other aspects of cell biology important for neurons.  So for example, neurons don’t divide.  Neurons have to very tightly regulate the material in their cell and to recycle it, and reuse it.  And so, we’re starting to investigate differences that may occur in these neurons from a Parkinson's patient to mean they're not as able to recycle and reuse their cellular components as well as a healthy neuron might. 

Another difference there maybe is the way the neurons make and generate, and supply energy.  So, there's a type of component of a cell called a mitochondrion.  That’s the energy factory.  It makes energy and there's been a suspicion for a long time that the mitochondria of a Parkinson's patient just might not be quite as good, so we’re starting to study a whole range of aspects of neuron biology in patients, in control cell lines, to better understand why those neurons die.  And only when you understand how they die can you think how you might protect them.

Hannah -   So these skin cells that have been turned into nerve cells, could they be used to help identify people who are at high risk of developing Parkinson's decades down the line?

Richard -   So, that’s a great idea.  So, the exciting aspect about these stem cells and the neurons that you make is that they're unique to the patient that you’ve made them from.  So yes, we would be able to try and correlate perhaps proteins secreted from these neurons and how that might be different proteins secreted from a patient neuron compared to a control neuron.

In order to find out more about the mood symptoms that Alan mentioned and the progression of Parkinson's disease, I return to speak with neurologist Dr. James Rowe from Cambridge University...

James -   Depression, and the other mood problem of anxiety, are extremely common with Parkinson's disease.  There are a lot of questions unanswered.  The first is that, is it more common than you would expect in people of a similar age?  Is the depression a reaction in some people against having what is essentially bad news?  Is it a reaction to having a restriction on your lifestyle, in your expectations of a happy and active retirement?  Or could it be something more that the illness itself is leading to depression?  One of the challenges we face is it’s not clear whether the usual approach is the treatment of depression that you might take in younger adults without Parkinson's disease, whether they work as well in patients with Parkinson's disease.

Hannah -   Can you tell us a little bit about the research that’s going on here in Cambridge in the area of Parkinson's?

James -   So that with a very active research clinic here, we’re treating patients really from Cambridgeshire and surrounding counties, and it covers a diverse range of project.  One of them is to really try and understand what the first symptoms of Parkinson's disease are, how it first affects the brain, with or within months of your symptoms coming on.  On that basis, we also want to try and understand what predicts how your Parkinson's disease would evolve.  Will you be someone who lives with it, Parkinson's disease, and remain fully active and independent over 10 or 15 years, or will you be someone who’ll get an early and aggressive dementia perhaps over the first couple of years?  Both of these things can happen. 

What we don’t yet understand is that is predicting and understanding why one individual takes route or the other so a lot of research on to that.  That’s linked to work on both treating some of the symptoms of Parkinson's disease and our emphasis is on treating the thinking and memory problems that can come with Parkinson's disease what are called cognition or enhancing cognition.  The other aspect is looking at treatments that might alter the course of the illness itself, fundamentally alter the course of the illness. 

What's increasingly clear and the focus for our research is that other chemicals in the brain that can be affected by Parkinson's disease, so two in particular.  We focus on one called serotonin that people might have heard of in connection with depression and mood anxiety.  Another chemical is noradrenalin, a brain’s version of adrenalin.  That’s also very important for clear thinking and flexibility.

It's time to take a look at the top stories from this month, I join PhD student David Weston from Cambridge University. He's been busy shifting through neuroscience research and comes up with his three favourite papers from the month....

David - So the first paper I would like to talk about has to do with memory. Now scientists have long thought that the birth of new brain cells within an area of the brain called the hippocampus, is really important for memory function. But exactly how these new brain cells work and how they integrate into the brain is something that researchers having been working hard over. Now a group of scientists based at the State University of New York in the USA have used a combination of viral and optogenetic techniques to find out just how important the growth of new brain cells within the hippocampus really is.

Hannah - So these scientists want to find out why these new-born cells are so important. How did they go about finding more about these cells?

David - Well they used a virus to deliver light-sensitive genes into new-born cells within the hippocampi of adult mice. Now this virus infects only the new-born cells and gives them these genes that produce proteins sensitive to light. The researchers were then able to control these cells by shining lights of different colours onto the cells to activate or deactivate them.

Hannah - So just by shining different coloured lights they could control whether these new-born cells were activated or deactivated. What did they do next?

David - Well what they wanted to do was see how important new cells within the hippocampus are for memory function. So first they showed that if they activated these new-born cells they could enhance synaptic plasticity, which is widely believed to correlate with better memory function. They then tried deactivating these cells and they found that the mice performed much worse is some tests of memory function.

Hannah - So the new-born cells definitely had something to do with memory formation.

David - Yes, but interestingly the effects of manipulating the new-born cells were only seen when the cells were 4 weeks of age, not when they were older or younger. These results hint at the idea that new cells within the hippocampus are able to exert their memory-enhancing effects only at early stages of their development.

Hannah - So this means that the timing of when new cells are born could play an important role in memory function and behaviour. Fascinating! What's your next paper?

David - The second paper I want to talk about also has something to do with timing. It's about how much of your life is affected by your time as a foetus. There is an increasing amount of evidence suggesting that many aspects of your adult health can be traced back to your aspects of your foetal environment and importantly your birth weight.

Hannah - So your weight at the time of you birth might be linked to things to do with your brain? How did the scientists in the study work that out?

David - So this group of scientists working across both Norway and the USA collected data from 628 adults, adolescents and children, measuring things like the thickness of their cerebral cortex, their brain volume and the surface area of their brain using scans taken in an MRI machine. They found that as birth weight increased the total brain size as an adult was much larger.

Hannah - So birth weight influences brain size, but why is this important?

David - Well low birth weight can influence your likelihood of getting some cognitive disorder such as autism, where you are five times more likely to get the disease. And while this study doesn't make any specific links between birth weight and disease it does show that brain development is heavily influenced by factors surrounding your birth.

Hannah - What's your final paper?

David - So the final paper this time is about a new drug that could help fight the effects of Alzheimer's disease. A collaboration between groups in Japan and Canada have taken an anti-diabetes drug and tested its ability to reverse some of the deleterious effects of the disease.

Hannah - How can a drug designed for diabetes treatment help with Alzheimer's Disease?

David - Well this drug, AC253, was originally part of a drug trial looking for potential targets for diabetes.  One of these targets is the amylin protein, which is similar to the toxic amyloid protein, that builds up in the brain and is a key target for Alzheimer's Disease.  This team had already shown that AC253 could block the formation of toxic amyloid protein and in this paper they showed that treating brain cells with this drug could reverse some of the effects of Alzheimer's.

Hannah - So these experiments were performed on cells in petri dishes, but how close could this be to a treatment for Alzheimer's disease in humans?

David - Well the authors themselves seemed quite optimistic about the prospect for a drug treatment. These results are encouraging because they show a reversal of Alzheimer's effects, which might mean things like being able to reverse a loss of memory!

We tackle some of your neuroscience questions. I joined Professor Simon Laughlin from Cambridge University who's been flexing his brain power to answer your questions about the brain.

Sean Hoskins got in touch via Facebook asking: "Can you burn off a hot fudge sundae by doing a difficult math problem instead of hitting the treadmill?"

Simon - The answer is definitely no. So, scientists wanted to measure oxygen consumption of the human brain, and test whether the brain was like a muscle - that if you worked it harder, it had to use more energy. And so, they got people to sit down and solve difficult math problems and measured their energy consumption of the brain. And what they found was that there was no detectable change.

So, doing difficult math problems will certainly not enable you to lose weight. The best thing you can use your brain for, is to design a good exercise regime and a diet.

Hannah - Thank you, Simon. I suppose I should be hitting the treadmill then in order to shed those Christmas pounds.