Build up of Calcium could lead to Parkinson's
Parkinson’s Disease is one of the commonest neurodegenerative diseases. It leads to difficulties with making movements and patients often also develop a characteristic tremor. In recent years scientists have discovered that a protein naturally present in the brain called alpha-synuclein appears to build up in some nerve cells and kill them, causing the disease; although why this happens, no one knew. Now, we do, thanks to a study by Cambridge scientist Gabi Kaminski. She’s found that the protein normally helps nerve cells to squirt out the neurotransmitter chemicals that enable neurons to communicate. As Chris Smith found out, it does this by temporarily soaking up some calcium, which makes it sticky, enabling it to link up with other alpha-synuclein proteins and squeeze out the neurotransmitter from the nerve ending. But as we age, both the protein and calcium tend to loiter for longer inside those nerve cells, making them more likely to form the toxic aggregates that go on to cause Parkinson’s.
Gabi - Parkinson’s disease is a neurodegenerative disease. That means people suffering from Parkinson’s disease will have a neuronal loss in a specific region of the brain. This has been linked to a protein called alpha-synuclein. This protein will form protein aggregates in the brain, and these protein aggregates can then kill off individual neurons and that is the problem.
Chris - So the outstanding questions then is we know this protein is linked to the disease, but we don’t know why it builds up and forms these aggregates that then poison the cells that are making it?
Gabi - Yes, that’s correct. We know it’s a relatively small protein and it’s very abundant at the so-called nerve endings; that’s where they squirt out chemicals that they use for neuron to neuron communication. You have little oily droplets that are called synaptic vesicles, and where these chemicals that do the chemical communication between neurons are packed into, it’s been known that this protein alpha-synuclein can bind to these oily little droplets and, thereby, help the release of these chemicals to then lead to neuron to neuron communication.
Chris - So that much was known, but what’s the unknown; what have you been able to discover?
Gabi - We wanted to understand how when there is a signal coming to the neuron that tells the neuron to release these chemical substances we know that there is a lot of calcium coming inside the cell. That is a very very crucial moment because the calcium concentration that is normally kept extremely low inside the cell is suddenly rising to really high concentrations. What we found was that there is a region within the alpha-synuclein protein that is highly negatively charged. That means the positive calcium ions can bind to this negatively charged protein and then can really help the clustering of these oily droplets, these vesicles, at the membrane and help the release of these chemicals.
Chris - Is it fair to say then, it’s a little bit like me squeezing an orange? Basically the calcium comes into the nerve ending, it sees this negative chunk of alpha-synuclein protein and the calcium all sticks and clusters around the negative charges because the calciums a bit positive and it’s attracted to it that what this then does is encourage the alpha-synuclein to squeeze those vesicles because it can get close to them, and that encourages the nerve chemical to come out, and that facilitates the passage of nerve information?
Gabi - Yes, exactly. This is really an important mechanism and we’ve now had the tools to study that because we have now access to what is called super resolution microscopy. We can really look at what individual alpha-synuclein molecules are doing inside a nerve cell and that is really exciting.
Chris - Indeed. We now have, thanks to you, a much clearer idea as to what this protein is doing - what its normal job is, why it’s there, but why does that then turn into the thing that we started discussing which is Parkinson’s disease? What makes it then build up into these toxic aggregates that kill cells?
Gabi - Yeah, that’s really an interesting point. The highest risk factor of developing Parkinson’s disease is age and, as we age, our metabolism is slowing down so this protein turnover is significantly slowed down. If we have too much of that protein it has a tendency to then become very sticky and if there are more proteins coming together, the chances are increased. Another problem is you might get a bit too much of the calcium coming in because the cell is too weak to get rid of all the calcium that is coming in.
Chris - Critically though, can you stop it?
Gabi - That's a very interesting question. And I think we’re getting a step closer here because this calcium binding region on the alpha-synuclein protein becomes now a really interesting region for small molecule drugs to bind to them. We think that this would prevent the aggregation. The other important finding that we have, we could show that if you treat the cells with the calcium channel inhibitors this might also be beneficial to patients. So there is hope.