Lewy bodies (LBs) are clumps of a protein called α-synuclein found in brain cells and are a vital feature of Parkinson’s disease (PD). However, scientists still haven’t found a way to create a cell model to study how LBs form. Recent studies suggest that problems with the immune system might play a role in the development of Parkinson’s disease.
Understanding why and how they form is essential to develop better treatments. In collaboration with its Early Drug Discovery Unit, scientists from the Neuro (Montreal Neurological Institute-Hospital) of McGill University have recreated Lewy bodies’ growth in human neurons and studied how they form. They found that immune challenges play a vital role in this process, revealing a new connection between the immune system and neurological diseases.
For this study, scientists used human stem cells to create Lewy bodies in living dopaminergic neurons, the kind of cells especially at risk in PD.
The scientists incubated human neurons with alpha-synuclein, the protein found in Lewy bodies, and triggered an immune reaction. They found that Lewy bodies only formed in dopaminergic neurons when both alpha-synuclein levels rose, and there was immune stimulation; without the immune challenge, no Lewy bodies appeared.
Credit:
Armin Bayati from Peter McPherson Lab, The Neuro
Additionally, when they tested other types of cells, like cortical neurons, they did not see Lewy body formation, indicating that this process is specific to dopaminergic neurons.
By observing the development of Lewy bodies in real-time, the scientists discovered that the immune response disrupts autophagy, the process that removes damaged cell materials.
They also noted that in dopaminergic neurons, Lewy bodies are membrane-bound and contain other organelles and membrane fragments, challenging the earlier belief that they were made solely of misfolded proteins.
This is the first study to demonstrate that both alpha-synuclein and an immune response are essential for Lewy body formation and that this effect is specific to dopaminergic neurons. It also offers significant information on Lewy body formation and structure, which could be important to future drug development.
Peter McPherson, a researcher at The Neuro and the study’s senior author, said, “Replicating Lewy body formation in living neurons is a significant step forward to understanding key aspects of Parkinson’s and another neurological disease. These neurons came from stem cells of healthy patients, suggesting anyone can develop Parkinson’s if exposed to the right environment, so a genetic predisposition to disease may not be necessary.”
Armin Bayati, a PhD candidate in McPherson’s lab and the study’s first author, said, “The results support previous research showing that an immune response plays an important role in Parkinson’s development. Future studies should focus on understanding how inflammation caused by an overexcited immune system causes Lewy body formation when coupled with α-synuclein.”
Journal Reference:
- Bayati, A., Ayoubi, R., Aguila, A. et al. Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines. Nat Neurosci (2024). DOI: 10.1038/s41593-024-01775-4