What happens to the brain in Parkinson’s?
Parkinson’s is the world’s fastest growing neurological condition, with 12 million projected to be living with it by 2040. But what is going wrong inside the brain and how can we stop it?
Parkinson’s develops when cells in a particular part of the brain — called the substantia nigra — stop working properly and are lost over time. These brain cells produce a chemical called dopamine and play a central role in coordinating movement.
Symptoms start to appear when the brain can’t make enough dopamine to control movement properly.
There are 3 main symptoms — tremor (shaking), slowness of movement and rigidity (muscle stiffness) — but there are many other symptoms too.
Parkinson’s is progressive, it gets worse over time. That’s because more and more brain cells become affected and stop working properly.
How and why brain cells get ‘Parkinson’s’ is a question that researchers have been trying to answer for decades. If we can find the answers, and understand what is happening inside the brain, we will be able to create treatments that can stop Parkinson’s in its tracks.
We don’t have all the answers yet, but we now understand some of the key things that go wrong with brain cells that are damaged and lost in Parkinson’s.
Let’s take a look at some of these now.
In the late 1980’s scientists funded by Parkinson’s UK studying brain tissue from people with Parkinson’s first spotted problems with mitochondria inside cells in the substantia nigra.
Mitochondria are like tiny batteries that are present inside almost every cell in our bodies. Their job is to convert fuel from our food into energy. Brain cells have thousands because they are so large and so busy sending the messages to control everything we do. As a result, our brains use up around 20% of all the energy our bodies generate.
When mitochondria don’t work properly, they can’t produce enough energy and this means cells stop working properly too. Even worse, broken mitochondria actually become toxic to cells and poison them.
Since this initial discovery, scientists have continued to study mitochondria in Parkinson’s to try and understand these problems better and figure out ways to fix them using new drugs.
Proteins are the building blocks of our bodies. A bit like making things with lego, our cells are built with proteins of different shapes and sizes. Cells are constantly making new proteins and recycling old ones to keep themselves healthy and working well.
But in Parkinson’s, and many other neurodegenerative conditions, proteins seem to misbehave. Large bundles of proteins (called Lewy bodies) were first seen inside brain cells from people with Parkinson’s in 1912 by German scientist Friedrich Lewy.
While we’ve known about Lewy bodies for over a century, we are still not completely sure how they might be contributing to the problems inside brain cells in Parkinson’s. Some scientists believe these masses of tangled up proteins clog up brain cells and cause damage, others think they may be benign — a symptom rather than a cause of major problems inside cells.
In 1997, two major discoveries highlighted one protein in particular that may play a key role in Parkinson’s.
Researchers identified that alpha-synuclein is the main protein found in Lewy bodies. And a separate study found that a change in the gene that makes alpha-synuclein causes a rare inherited form of Parkinson’s.
Further research has revealed that mis-shapen forms of alpha-synuclein build up inside the brain cells affected in Parkinson’s.
These distorted proteins may not only be toxic but may also be responsible for the spread of the condition as the protein leaks out of affected brain cells and enters neighbouring cells.
As a result of these discoveries, there is now huge focus from the pharmaceutical industry to create treatments that can help the brain to identify and remove toxic forms of alpha-synuclein.
As mentioned previously, our cells are constantly recycling their proteins. Old and unwanted proteins are dismantled and the parts are used to make new proteins that the cell needs. A bit like taking an old car apart and using its components to make a new one.
The task of ‘dismantling’ of old proteins is carried out by lysosomes and proteasomes, which break up proteins that have been ‘put out’ for recycling.
Important clues that problems with recycling may be central to the development of Parkinson’s have come from studying the genetics of the condition.
The two most common genetic forms of Parkinson’s are caused by changes in the GBA1 and LRRK2 genes.
The GBA1 gene provides the instructions to make a protein called glucocerebrosidase (or GCase) which is found in lysosomes. Experiments show that when there is a change in this gene, the GCase protein doesn’t work properly. This decreases recycling and increases levels of damaging alpha-synuclein.
Meanwhile, the LRRK2 gene provides the instructions to make the LRRK2 protein. This protein appears to be involved in many activities inside brain cells, including recycling.
Recycling is a complex process and we know that our cells become less efficient as we get older. Problems with recycling may contribute to the build up of unwanted proteins like alpha-synuclein and damaged mitochondria — which can overwhelm brain cells. So making recycling work more efficiently is an exciting avenue for developing new treatments.
Inflammation is the body’s defence system to protect itself from harm and repair tissue damage. If we bump or cut ourselves, our immune system sends in its troops to get rid of unwanted invaders and start the healing process. And we might notice the signs of inflammation — like swelling, redness and soreness. Once, it’s job is done, the immune system retreats and the inflammation disappears.
The same thing happens when we get ill with a viral or bacterial infection. Our immune system kicks in, raising our temperature to try and kill off the infection.
Our immune systems and the inflammatory process is absolutely critical. Without it, small cuts would get infected and any infection could prove deadly.
But sometimes our immune systems get confused and trigger an immune response when it isn’t helpful. A constant state of inflammation can actually cause damage to our cells and organs. This is what happens in conditions like rheutmatoid arthritis, where inflammation in joints causes pain, stiffness, and mobility problems. And there is evidence that in Parkinson’s something similar is happening inside the brain.
The immune response inside the brain is mainly controlled by cells called microglia and astrocytes. These cells are not responsible for communicating messages, like the dopamine-producing cells affected in Parkinson’s. Instead their job is to support and protect other brain cells.
In Parkinson’s, microglia and astrocytes trigger excessive and chronic inflammation which is believed to contribute to and possibly accelerate the damage to dopamine-producing brain cells.
However, why this happens is still unclear. It could be in response to cells dying and releasing toxins, it could be that toxic forms of alpha-synuclein might also play a role and it could even be that inflammation elsewhere in the body is contributing, especially in the gut.
As a result, researchers and companies are now developing new treatments for Parkinson’s that aim to dampen down harmful inflammation in the brain.
Piecing together the clues
While we’ve made phenomenal progress in understanding what’s happening inside the brain in Parkinson’s there is still a lot we don’t understand.
One major question that scientists are grappling with is what goes wrong first? And how do all these different processes combine to cause Parkinson’s?
Is it problems with mitochondria and energy production that cause recycling to stop working properly, which means proteins build up and this triggers inflammation? Or is it some other sequence?
Understanding this chain of events and how things fit together is crucial to figuring out where and when to intervene with new treatments. Do we need to create treatments that tackle all of them?
Another major question is: do the same things go wrong in the same way in everyone with Parkinson’s?
We know that Parkinson’s is a very individual and variable condition — and that there may be different types. Could it be that actually different problems inside brain cells are causing these different forms of the condition? And do these different forms need different treatments?
There is still much more to learn and understand but what we’ve uncovered so far is already leading to treatments with the potential to slow, stop or reverse Parkinson’s.
Help deliver new treatments, faster
At Parkinson’s UK, we fund research to explore why and how the condition starts and progresses, alongside work through our pioneering Virtual Biotech to develop and test game-changing new treatments.