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New results from a collaborative Oxford Parkinson’s Disease Centre and Cardiff University study on the cellular origins of Parkinson's could be key to developing new treatments.

The OPDC logo featured with prominent OPDC researchers Prof Caleb Webber and Prof Richard Wade-Martins

Scientists have uncovered new insights into the origins of Parkinson’s. The team, from the UK Dementia Research Institute at Cardiff University and the Oxford Parkinson’s Disease Centre, studied the genes of more than 6,000 cells from a region deep in the middle of the brain called the substantia nigra, which is where many neurological diseases begin.

In particular, they were interested in the dopaminergic neurons in this region, cells which are known to play a key role in the regulation of movement and cognition and whose loss results in Parkinson’s. Up to now, it has been unclear whether immune cells of the brain, the microglia, are responsible for causing the loss of these neurons, as has been observed in Alzheimer’s.

The results of this latest study suggest that, unlike Alzheimer’s, the cause of Parkinson’s can be found directly within the dopaminergic neurons. Researchers believe this could be the key to developing new treatments.

Professor Caleb Webber, who led the study and is based at the UK Dementia Research Institute at Cardiff University, said: “This research has huge implications for our understanding of Parkinson’s as it tells us where to look for the problem. With the growing recognition of role of the microglia and subsequent neuroinflammation in Alzheimer’s, many scientists have been asking whether neuroinflammation also has a major role in causing Parkinson’s disease too.

“However, our findings clearly point away from that idea, suggesting that we need to refocus our efforts into what is going wrong in the dopaminergic neurons early on in Parkinson’s brains in order to find treatments. 

Parkinson’s is the second most common neurodegenerative disorder after Alzheimer’s and leads to involuntary shaking of particular parts of the body, slow movement and stiff and inflexible muscles.

As part of their work to map all the cells contained within the substantia nigra, the research team looked at the genes in regions of DNA that had been associated with increased risk of a person developing Parkinson’s and asked whether these genes were switched on in any particular type of cell. Indeed, they found a large number of these genes are switched on in dopaminergic neurons, suggesting that the problem arises directly within these cells.

Previous research has shown the genetic risk for Alzheimer’s most significantly influences microglia, immune cells which can cause inflammation of the brain.

Professor Webber added: “The substantia nigra is an area of the brain that has been sorely understudied compared with the neocortex, where research has comprehensively mapped and characterised the diverse cell-type populations and identified cells associated with certain diseases. Further studies such as this one are needed to provide insights into the potential causes of Parkinson’s diseases as well as other neurological disorders.”

Professor Richard Wade-Martins, head of Oxford Parkinson’s Disease Centre, who led the work at Oxford, said: “When developing therapies to prevent the disease and stop cells dying it is essential to know which cells we should target. This work confirms the importance of directing our work at the dopamine neurons. This work is an excellent example of collaborative work by scientists coming together across different centres bringing their different skill sets together.”

Professor Bart De Strooper, Director of the UK Dementia Research Institute, said: “With the UK’s prevalence of Parkinson’s disease expected to almost double by 2065, the need for breakthroughs in treatment is imperative.

Only by investing in discovery research such as this, are we able to uncover the key disease processes behind the conditions that cause dementia.

It is my hope that this innovative work from our researchers in Cardiff and the team at the Oxford Parkinson’s Disease Centre, moves us closer to life-changing therapeutics and relief for the thousands affected by this devastating condition.”

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK, said: “This intriguing study underlines the importance of collaborative research taking place through a number of strategic initiatives funded by Alzheimer’s Research UK. This approach means we can identify and target gaps in our knowledge and barriers to progress, ensuring we tackle diseases that cause dementia in the most effective way and from every angle.”

 

The full paper, “A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders,” is available to read in Nature Communications.