Kavli Oxford researchers discover how brain immune cells protect neurons by ‘nibbling’ away harmful material

Kavli Oxford researchers discover how brain immune cells protect neurons by ‘nibbling’ away harmful material

Scientists at the Kavli Institute for Nanoscience Discovery, University of Oxford, have uncovered a previously unrecognised protective mechanism in Parkinson’s disease, revealing how the brain’s immune cells can selectively ‘nibble’ away portions of neurons containing harmful protein aggregates without destroying the cells.

3D reconstruction of Airyscan super-resolution image of MG cocultured with DANs under fibril-seeded conditions, showing the presence of pSyn+ puncta and MAP2+ puncta in CD68+ MG. Image: HungJu Chueh, Molecular Neurodegeneration Research Group

The study, published in Science Translational Medicine, was led by Kavli Oxford’s Professor George Tofaris, with Dr HungJu Chueh as first author. Their findings reveal how microglia, the brain’s resident immune cells, can remove harmful material from neurons without destroying the cells themselves.

Parkinson’s disease affects more than 10 million people worldwide and is characterised by the progressive loss of dopamine-producing neurons. One of its key features is the accumulation of abnormal clumps of a protein called alpha-synuclein within nerve cells.

Although microglia are known to play an important role in maintaining brain health, their activity in neurodegenerative diseases can be both protective and harmful. Understanding how to support their beneficial functions could offer new opportunities for developing treatments that slow disease progression.

How microglia protect neurons

Using human stem cell-derived models, the researchers studied interactions between dopamine-producing neurons and microglia when harmful alpha-synuclein aggregates accumulated inside neurons.

They discovered that microglia could selectively remove small portions of neurons containing these aggregates through a process known as trogocytosis, in which one cell effectively ‘nibbles’ material from another.

Crucially, this process enabled microglia to reduce the accumulation of harmful protein aggregates without engulfing or destroying the neurons themselves.

Dr Hung-Ju Chueh, first author of the study, explained: ‘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.’

The researchers also identified signalling pathways involving P2RY12 and CD22, alongside an IL-10-mediated negative feedback mechanism that regulates microglial trogocytosis.

Using single-cell RNA sequencing, the team also identified a distinct population of activated microglia associated with this protective response, providing further insight into the protective functions of the brain’s immune cells in Parkinson’s disease.

A further finding was the role of a protein called GPNMB, which appears to be important in enabling microglia to clear harmful alpha-synuclein aggregates. Genetic variation in the GPNMB gene has previously been linked to Parkinson’s disease, but its functional contribution has remained unclear.

The researchers found increased levels of GPNMB in microglia exposed to neurons containing alpha-synuclein aggregates. They also observed increased GPNMB in microglia within the substantia nigra, a brain region particularly affected by Parkinson’s disease, in tissue from individuals with Parkinson’s disease or incidental alpha-synuclein pathology.

When the team reduced GPNMB expression using a genetic technique known as CRISPR interference, microglia became less effective at removing the aggregates, providing further evidence of its protective role.

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.’

The findings provide new insight into how interactions between immune cells and neurons may influence the progression of Parkinson’s disease. While further research is needed to establish how these mechanisms could be harnessed therapeutically, the study highlights the potential of targeting protective microglial responses.

The research was supported by the Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre.

Read the research: Human microglia clear intraneuronal α-synuclein aggregates by GPNMB-mediated trogocytosis, published in Science Translational Medicine. Authors: Hung-Ju Chueh, Antigoni Katsikoudi, Ana Aragón-González, Chor Lai Lam, Liezel Tamon, Ashwin Jainarayanan, Devika Agarwal, Sally A Cowley, David Sims, and George K Tofaris.