Researchers at the University of Oxford have uncovered a previously unrecognized protective role for microglia, the brain’s resident immune cells, in Parkinson’s disease, according to a study published on News-Medical.net. The research demonstrates that a distinct population of human microglia can selectively remove harmful clumps, or aggregates, of the Parkinson’s-causing protein alpha-synuclein from dopamine-producing neurons.
Parkinson’s disease is a neurodegenerative disorder currently without a cure that affects more than 1% of the global population over the age of 60, characterized pathologically by the degeneration of dopaminergic and other neurons alongside the formation of intraneuronal filamentous inclusions composed of alpha-synuclein, as detailed in research published on PubMed Central.
Investigating Microglial Interaction with Neurons
The study was funded by the Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Oxford. Investigators examined how microglia respond when alpha-synuclein aggregates form inside neurons, either resulting from increased alpha-synuclein gene dosage or following exposure to alpha-synuclein fibrils that act as templates to encourage endogenous neuronal protein misfolding.
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, stated Dr. Hung-Ju Chueh, first author of the study.
Laboratory models utilizing human induced pluripotent stem cell (iPSC)-derived co-cultures under pathological conditions revealed that healthy human microglia sense and remove small aggregates developing de novo inside neurons at both axonal terminal and somatodendritic compartments without causing neuronal injury. When assessing larger, established aggregates using co-cultures derived from unrelated healthy iPSC lines, continuous treatment with a low, non-toxic dose of the lysosomotropic agent chloroquine blocked aggregate clearance, indicating that clearance occurs through a lysosomal or phagocytic mechanism.
Cellular Pathways and the Role of GPNMB
Using single-cell RNA sequencing to analyze individual cell gene profiles, the research team identified a subpopulation of activated microglia exhibiting diverse morphologies—including ramified, bipolar, amoeboid, and rounded forms—that correlated with this beneficial clearance response. Genes such as APOE, TLR4, LPL, and CD68 were upregulated in microglia co-cultured with fibril-seeded neurons. This microglial activation was found to be TREM2-independent and involved contact mediated by P2RY12 and CD22, alongside a self-regulated brake mediated by the cytokine IL-10 to prevent tissue damage.
The protein glycoprotein non-metastatic melanoma protein B (GPNMB) was found to be an important component of this protective mechanism. While genetic variation at the GPNMB locus has previously been linked to Parkinson’s disease through genome-wide association studies, its functional role remained unclear. The Oxford team discovered that GPNMB was upregulated and interacted with pathological alpha-synuclein within microglia exposed to aggregate-containing neurons. GPNMB was also elevated in substantia nigra microglia—the brain region most affected in Parkinson’s disease—in human tissue samples from individuals with incidental alpha-synuclein pathology or Parkinson’s disease. When researchers selectively reduced GPNMB expression using CRISPRi genetic approaches, the cells exhibited reduced effectiveness in clearing alpha-synuclein aggregates.