Mutated brain defenders likely factor of early-onset Parkinson’s disease
![Mutated brain defenders likely factor of early-onset Parkinson’s disease](http://biologicalsciences.leeds.ac.uk/images/resized/750x375-0-0-1-80-Activated_microglia__right__and_dormant_human_microglia_permissions_Dr_Marine_Krzisch_800x400.png)
A mutation in a brain defender cell is likely contributing to the progression of early-onset Parkinson’s disease, a new study shows.
The study, led by scientists at the University of Leeds and the Whitehead Institute for Biomedical Research in Massachusetts, USA reveals that microglia found in the brain and nervous system can carry a mutation involved in early-onset Parkinson’s, called A53T, which encourages these cells to damage other brain cells, such as neurons (messengers of the brain).
Early-onset Parkinson’s is caused by genetic mutations, whereas late-onset Parkinson’s disease cases are not inherited.
The results of this study suggests that this mutation makes microglia more toxic to neurons, which likely worsens cell damage seen in early-onset Parkinson’s disease.
What are microglia?
Microglia are immune cells found in the brain and central nervous system, including the spine. They patrol the brain environment identifying and clearing out pathogens, and helping to regrow brain tissue.
They are very active, even in a non-diseased state, and are very flexible in structure which enables them to quickly defend the brain at short notice.
Microglia’s role in Parkinson’s disease
In Parkinson’s disease, it is thought that microglia become hyper-alert. This is called activation. However, their exact role remains unclear.
In the study, scientists tested whether human microglia carrying the A53T mutation are more activated than microglia that do not carry the mutation to see if they could draw links between disease and activity of microglia.
To do this, they used two different systems to produce human microglia: traditional cell culture (where cells are grown outside of their natural environment, such as a lab) and transplanting human microglia into a mouse brain.
This latter approach allowed scientists to produce human microglia which look and behave more like microglia in the human brain.
In the study, scientists were looking for indicators of microglial pro-inflammatory activation, including the proteins Iba1, CD68 and p65.
Their tests revealed that when stimulated, human microglia carrying the A53T mutation involved in early-onset Parkinson’s show increased levels of Iba1, CD68 and p65 compared to microglia that do not carry the mutation. This suggests that human microglia carrying the A53T mutation are more prone to becoming hyper-alert and damage neurons when they are stimulated.
Overactivation of microglia isn’t the only cause of neuron death in Parkinson’s. But if we can decrease their activation, it will help us get to the point where we can slow down or actually stop the disease.
![Microglia activation timeline
4 microglia are lined up in a horizontal row. They are green shapes on a black background. In their ramified state (left), they are stretched branched shapes. In their ameboid state (right), they are round.](http://biologicalsciences.leeds.ac.uk/images/resized/750x375-0-0-1-80-Microglia_activation_timeline_1200x400_permissions_Dr_Marine_Krzisch.png)
An additional discovery
When unstimulated, human microglia carrying the A53T mutation have decreased levels of catalase, an antioxidant enzyme that fights harmful molecules.
The decreased levels of catalase in these microglia may explain their higher activation when stimulated.
Dr Krzisch explains:
This is because catalase removes hydrogen peroxide, which is produced during microglial activation and may further trigger it. In absence of catalase, hydrogen peroxide accumulates into the cells, and this may lead to their hyper activation.
Future research in Parkinson’s disease
Understanding the impact of A53T mutation on microglia may shed light on the development of Parkinson’s disease, as it provides a well-controlled way to assess the dysfunction of these cells in inherited cases.
However, as most cases of Parkinson’s disease are spontaneous and unexplained, and do not involve this mutation, Dr Krzisch stressed that future research should explore the extent to which their findings translate to cases of Parkinson’s disease which aren’t inherited.
The study, The A53T mutation in α-synuclein enhances pro-inflammatory activation in human microglia upon inflammatory stimulus, can be found in Biological Psychiatry.