Researchers at the University of Oxford have uncovered a previously unrecognised protective role for microglia, the brain’s resident immune cells, in Parkinson’s disease.
The study, funded by the Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Oxford, shows that a distinct population of human microglia can selectively remove harmful clumps (aggregates) of the Parkinson’s-causing protein alpha-synuclein from dopamine-producing neurons.
Parkinson's disease affects more than 10 million people worldwide. The disease is characterised by the progressive loss of dopamine-producing neurons and the build-up of abnormal clumps of the protein alpha-synuclein within nerve cells. Identifying new potential ways of preventing or removing these clumps could enable new treatments to slow or stop the progression of Parkinson’s disease.
Microglia are the brain’s resident immune cells, acting as its first line of defence and helping to keep the brain healthy. They respond to damage, clear away cellular debris and help shape connections between nerve cells, but when persistently activated they can contribute to inflammation and damage to neurons.
The researchers developed human stem cell models (derived from induced pluripotent stem cells (iPSCs)) allowing human dopamine-producing neurons and microglia to be studied together. The team examined how microglia responded when alpha-synuclein aggregates formed inside neurons, either as a consequence of increased alpha-synuclein gene dosage or after exposure to alpha-synuclein fibrils which act as a ‘template’, encouraging the endogenous neuronal protein to misfold the same way.
The researchers found that microglia were able to reduce the harmful alpha-synuclein aggregates associated with Parkinson’s disease by selectively removing small portions of the neuron through a process known as trogocytosis, where cells “nibble” material from another cell.
This reveals a new mechanism through which microglia can remove harmful material while preserving the overall structure and function of the neuron.
Dr Hung-Ju Chueh , first author of the study, said: “What is striking is the precision of this response. The microglia were not simply engulfing damaged neurons but instead removing parts of the neuron containing aggregated alpha-synuclein, suggesting that, at certain stages of disease, microglia help neurons dispose of potentially harmful material.”
This response was fine-tuned by both sensing (P2RY12) and inhibitory (CD22) signals between the two cell types, as well as a “self-regulated brake” on microglia mediated by the cytokine IL-10, which stops them from damaging healthy tissue.
Using single-cell RNA sequencing, a technique that allowed them to examine the gene profiles of individual cells, the researchers identified a subpopulation of activated microglia associated with this beneficial clearance response.
Professor George Tofaris , senior author of the study, said: “Our findings highlight that the immune response in Parkinson’s disease is more nuanced than simply being beneficial or harmful.
"We have identified a population of human microglia that can actively remove pathological alpha-synuclein from neurons. Understanding how to enhance and monitor such beneficial microglial functions, without triggering damaging inflammation, could open up new avenues for developing disease-modifying treatments.”
Professor Tofaris adds that “We also found that the protein glycoprotein non-metastatic melanoma protein B (GPNMB) appears to be an important part of this protective. Genetic variation at the GPNMB locus has previously been associated with Parkinson’s disease through genome-wide association studies, but the functional role of GPNMB in disease has remained unclear.”
The researchers found that GPNMB was upregulated and interacted with pathological alpha-synuclein within microglia when they were exposed to neurons containing aggregates. GPNMB was also increased in microglia within the substantia nigra, the brain region most affected in Parkinson’s disease, in tissue from individuals with incidental alpha-synuclein pathology or Parkinson’s disease.
When the researchers selectively reduced GPNMB expression in microglia using genetic approaches (CRISPRi), the cells became less effective at clearing alpha-synuclein aggregates from neurons, providing evidence that GPNMB plays an active role in this protective process.
ENDS
The full paper , Human microglia clear intraneuronal alpha- synuclein aggregates by GPNMB-mediated trogocytosis, can be read in Science Translational Medicine
For further information or interviews with the researchers, please contact:
Chris McIntyre
Communications Manager (Research & Innovation)
University of Oxford
tel (direct): 01865 270 046
tel (News Office): 01865 280528
Christopher.mcintyre@admin.ox.ac.uk
About the Nuffield Department of Clinical Neurosciences
The Nuffield Department of Clinical Neurosciences has an established research and teaching portfolio with a national and international reputation for excellence. It comprises six sections: the Centre for the Prevention of Stroke & Dementia, the Division of Clinical Neurology, the Brain Network Dynamics Unit, the Nuffield Division of Anaesthetics, the Nuffield Laboratory of Ophthalmology and the Oxford University Centre for Integrative Neuroimaging. The Department is largely based in the John Radcliffe Hospital and has developed a highly integrated and interdisciplinary environment in which research, teaching, clinical training and clinical care interact. This enables new approaches to the understanding, diagnosis and treatment of brain diseases.
About the NIHR
The mission of the National Institute for Health and Care Research (NIHR) is to improve the health and wealth of the nation through research.
We do this by:
NIHR is funded by the Department of Health and Social Care.
Our work in low and middle income countries is principally funded through UK international development funding from the UK government.
Science Translational Medicine
Experimental study
Cells
Human microglia clear intraneuronal alpha- synuclein aggregates by GPNMB-mediated trogocytosis
7-Oct-2026