Early Immune and Synaptic Changes Discovered in Parkinson's Disease

Parkinson's disease is considered the second most common neurodegenerative disorder worldwide. A key feature of the disease is the presence of so-called Lewy bodies—deposits of the protein alpha-synuclein in the brain. For a long time, these were thought to be the primary cause of the death of dopaminergic neurons. However, a study published in *Nature Communications* by a research team from LMU Munich and the German Center for Neurodegenerative Diseases (DZNE) paints a much more complex picture.

The researchers examined human brain tissue from various stages of Parkinson’s disease and compared it with tissue from people with Alzheimer’s disease—both with and without Lewy body pathology. Their focus was on dopaminergic cells—that is, cells that produce and release dopamine and play a key role in motor function, motivation, reward, and cognition.

The Significance of Lewy Body Pathology

The analyses show that the amount of misfolded alpha-synuclein is closely associated with the loss of dopaminergic neurons in classic Parkinson’s disease. Surprisingly, however, this correlation does not apply to patients with Alzheimer’s disease and additional Lewy body pathology. Despite comparable alpha-synuclein deposits, no neuronal loss is observed in these patients. These results suggest that Lewy body pathology alone does not explain the neurodegeneration. Rather, the disease context appears to be decisive in determining whether alpha-synuclein actually has a neurotoxic effect.

“Our findings show that alpha-synuclein cannot be considered in isolation. Its interaction with other pathological changes in the brain is crucial,” says study leader PD Dr. Thomas Köglsperger of the Department of Neurology at LMU Medical Center in Munich.

Changes begin long before nerve cells are lost

The findings from the earliest stages of the disease are particularly significant. Even in individuals with so-called incidental Lewy body disease—a condition considered a precursor to Parkinson’s disease—the researchers found distinct changes in the brain’s synapses. Even before classic Lewy bodies can be detected in the substantia nigra, activation of the complement system and a selective loss of inhibitory synapses are evident. These changes suggest an early immune-mediated reorganization of neural networks that precedes Lewy body pathology and the actual loss of nerve cells.

New Approaches to Biomarkers and Therapies

The study thus provides insights into previously unknown early disease mechanisms. Immunological changes and synaptic remodeling processes could serve as biomarkers in the future to detect Parkinson’s disease as early as its prodromal stage. At the same time, they open up new therapeutic possibilities that target not only alpha-synuclein but also early inflammatory and synaptic processes.
“If we can specifically influence these early changes in the future, there is a chance to slow the progression of the disease much earlier—possibly even before irreversible nerve cell loss occurs,” says Köglsperger.

The Study

For this study, the researchers combined spatial transcriptomics, spatial proteomics, and alpha-synuclein seeding assays on human postmortem brain tissue. This allowed them to investigate molecular changes with unprecedented spatial resolution and identify new mechanisms underlying the development of Parkinson’s disease.

Originalpublikation: Rumpf, SL., Strübing, F.L., Nalbach, K. et al. Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies. Nature Communicaitons (2026). DOI: https://doi.org/10.1038/s41467-026-74961-6