Scientists use stem cells to recreate a hallmark of Parkinson’s disease in human neurons

Lewy bodies are a hallmark of Parkinson’s disease (PD) and other related neurological conditions. Understanding why and how they develop is essential to developing better treatments.

A study from McGill University’s Neuro (Montreal Neurological Institute-Hospital), in collaboration with its Early Drug Discovery Unit, recreated the growth of Lewy bodies in human neurons and tracked their formation to gain insights important on why and how they form. The scientists published their results in the journal Natural neuroscience on October 8, 2024.

Above all, they discover that the immune challenge is important for this process, identifying a previously unknown link between the immune system and neurological diseases.

Lewy bodies are thought to result from the accumulation of misfolded proteins in neurons. Previously, the only way to study them in human neurons was through brain autopsy, which is not ideal because the cells decay quickly after death. In this study, neuroscientists used human stem cells to create Lewy bodies in living dopamine neurons, the cell type particularly at risk in PD.

To do this, the scientists incubated the neurons with a protein called alpha-synuclein, present in Lewy bodies, and coupled it with an immune response.

The results reveal that Lewy bodies develop only when dopamine neurons are exposed to both increased alpha-synuclein and immune stimulation. Without the immune challenge, no Lewy body would develop. Additionally, performing the same procedure on other cells, such as cortical neurons, does not produce Lewy bodies, suggesting that this effect is specific to dopamine neurons.

By following the development of Lewy bodies in real time, scientists discovered that in dopaminergic neurons, the immune response impairs autophagy, that is, the elimination of damaged cellular materials. They also found that in these cells, Lewy bodies are membrane-bound and contain other organelles and membrane fragments, contradicting previous dogma that Lewy bodies were composed exclusively of misfolded proteins.

This study is the first to show that alpha-synuclein and an immune response are necessary for the formation of Lewy bodies and that this effect is specific to dopamine neurons. It also provides important information about the formation and structure of the Lewy body, information that could be important for future drug development.

“Replicating the formation of Lewy bodies in living neurons represents an important step forward in understanding key aspects of Parkinson’s disease and other neurological diseases,” says Peter McPherson, a researcher at The Neuro and lead author of the study. “These neurons come from stem cells from healthy patients, suggesting that anyone can develop Parkinson’s disease if exposed to the appropriate environment, and that a genetic predisposition to the disease may not be the case. -not be necessary.”

“The results support previous research showing that an immune response plays an important role in the development of Parkinson’s disease,” says Armin Bayati, a Ph.D. candidate in McPherson’s lab and first author of the study. “Future studies should focus on understanding how inflammation caused by an overexcited immune system causes the formation of Lewy bodies when combined with α-synuclein.”