Calcium, good for your bones but bad for your brain?
Researchers have discovered an important interplay between alpha-synuclein and calcium inside cells, insight which could help us develop drugs that slow Parkinson’s. We go behind the headlines to find out more.
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Most people are familiar with calcium as a component of dairy products that helps keep our teeth and bones healthy. Bone health is an important consideration in Parkinson’s, studies have shown that those with the condition are more likely to have a lower bone density, which can lead to osteoporosis and put people at risk of fractures should they have a fall. But calcium also plays a vital and varied role in our biology and that of all other animals, plants and even fungi — helping cells to respond and adapt to their environment, and is essential for survival.
While we need calcium to keep our whole bodies not just our bones working, over the last decade it has become increasingly apparent that this element may have a hidden dark side.
The dark side of milk
As one of our main dietary sources of calcium, you might think that topping up your calcium levels with a glass of milk might be a good idea to keep your bones healthy. Milk has an added benefit as it is also high in vitamin D, which helps your bones to absorb calcium. However, large scale studies have suggested that drinking a large cup of milk per day may double your chances of developing Parkinson’s. So what’s going on, is calcium to blame?
Studies in Hawaii, the US and Greece and have consistently shown that milk consumption is linked with a slightly increased risk. Some studies have suggested that the risk seems to be specific to milk rather than other calcium containing foods — such as cheese, yogurt, ice-cream or non-dairy sources like cereals — and pointed towards the involvement of traces of pesticides in dairy products. More recently, low fat dairy products were called into question, and there have even been a number of studies suggesting that bacteria living in the gut may play a role.
While much more research is needed in this area to understand what is causing the association between dairy and Parkinson’s risk, it looks like calcium is not to blame. But is there another reason to be wary? In Parkinson’s, when it comes to keeping those dopamine producing brain cells healthy, could another type of calcium be causing a problem?
Calcium in the brain
We’ve known for some time that too much calcium causes problems for brain cells affected in the condition, inducing stress that leads to damage and eventually cell death. And there is evidence that drugs that block the channels that calcium uses to get into the cells affected by Parkinson’s helps to protect these precious cells. For instance, both apamin, a calcium-channel blocking chemical in bee venom, and isradipine, a calcium-channel blocker approved for treating high blood pressure, have been shown to slow the progression of Parkinson’s in animal models. And, in people, isradipine use has been linked to a slight reduction in risk of developing the condition.
Recently, research into calcium blockers in Parkinson’s has made it all the way to clinical trials, and the ability of isradipine to slow Parkinson’s is currently being tested in a large phase III, placebo controlled trial in the US and Canada called STEADY-PD, which is due to finish in 2019. But while the science is pointing towards this being an effective strategy to slow Parkinson’s, researchers aren’t exactly sure why calcium is so bad for dopamine producing brain cells and how it leads to cell loss.
Calcium and clumps
Previous studies have suggested a link between calcium and a protein called alpha-synuclein, commonly known as the main constituent of the sticky clumps of protein called Lewy bodies that form in cells affected by Parkinson’s. Like calcium, too much alpha-synuclein is also a bad sign for brain cells as we know it can also induce Parkinson’s-like problems in animal models. However, one of the unanswered questions is what the normal function of this protein actually is.
Researchers in Cambridge may have found the answer. Using ultra-high resolution microscopy techniques, they found that alpha-synuclein binds to the cellular packages called ‘vesicles’ containing the chemical messengers (like dopamine) that nerve cells release to communicate, and alter their movement within the cell. What’s more, the team discovered that alpha-synuclein plays a role as a calcium sensor, and in the presence of calcium, it changes its structure and causes vesicles to come together.
The researchers also looked at what happened when there was too much alpha-synuclein or calcium in the cell, as well as testing cells that were unable to store excess calcium effectively. The results point towards an important balance between alpha-synuclein and calcium inside cells, which when tipped (by too much calcium or too much alpha-synuclein) may cause the damage that ultimately leads to brain cell death. This insight provides a clue that could be the key to better treatments.
Towards a treatment that slows Parkinson’s
Stopping too much calcium from building up inside the cells may be the answer to reducing the ability of this chemical to cause damage, but there may still be one more obstacle to overcome and it’s all about side effects.
As we discovered, calcium has many roles in the body. Outside the brain one of it’s main roles is related to our heart and circulation — which is why calcium channel blockers are often used to treat heart disorders, including high blood pressure. They work by reducing the electrical activity within the heart, so reducing how hard the heart muscle is working, and also widen the arteries so reducing blood pressure and the effort required to pump the blood. So using calcium channel blockers to treat Parkinson’s could have side effects related to these effects outside the brain (including lowering blood pressure)— this is one of the factors that the STEADY-PD trial will be assessing — and it could restrict how much calcium blocking drug a person can be given.
But when it comes to reducing side effects of these medications there may be a solution. Calcium gets into our cells through a number of different channels, the ones that are particularly interesting for Parkinson’s are called CaV1.3, which is the channel adult dopamine producing brain cells primarily rely on. The calcium channel blockers that are available today, such as isradipine, currently target both CaV1.2 and CaV1.3 — they are not selective for the type of calcium channel that would likely have the most benefit in Parkinson’s. But developing a drug that is could be the answer to an effective calcium blocker for slowing the progression of Parkinson’s with fewer side effects.
Targeting calcium in our brain isn’t as simple as reducing dietary intake of foods high in calcium. So, if you were wondering whether to swap to black coffee or skip your morning bowl of cereal, it’s rather unlikely to have beneficial effect on the cells affected by Parkinson’s. And, when it comes to developing the condition, we know the benefits of eating these foods, particularly in terms of bone health, far outweigh the risks.
But drugs that target the calcium inside cells affected by Parkinson’s could have real potential. And, as we learn more about what’s happening inside our brain cells, it is likely this is one of the areas where researchers could develop new and better treatments.
