Stem Cells Recreate Parkinson’s Disease in Human Neurons

Lewy bodies are characteristic of Parkinson’s disease (PD) and other neurological disorders. Understanding why and how they arise is crucial for creating effective treatments.

A study conducted by McGill University’s Neuro (Montreal Neurological Institute-Hospital) in partnership with its Early Drug Discovery Unit replicated the growth of Lewy bodies in human neurons and tracked their formation to acquire significant insights into why and how they originate. The researchers published their findings in the journal Nature Neuroscience on October 8, 2024.

Crucially, they discover that immunological challenge is necessary for this process, revealing a hitherto unrecognized relationship between the immune system and neurological illness.

Lewy bodies are hypothesized to be caused by the accumulation of misfolded proteins in neurons. Previously, the only technique to investigate them in human neurons was via brain autopsy, which is not optimal because cells degrade quickly after death. In this study, neuroscientists employed human stem cells to generate Lewy bodies in live dopaminergic neurons, which are particularly vulnerable in Parkinson’s disease.

The researchers accomplished this by incubating neurons with a protein called alpha-synuclein, which is prevalent in Lewy bodies, and connecting it to an immunological response.

The findings show that Lewy bodies form only after dopaminergic neurons are exposed to both an increase in alpha-synuclein and immunological activation. Without the immunological challenge, no Lewy bodies formed. Furthermore, conducting the same process on other cells, such as cortical neurons, does not result in Lewy bodies, indicating that this effect is limited to dopaminergic neurons.

The scientists revealed that the immune response affects autophagy in dopaminergic neurons by tracking the growth of Lewy bodies in real time. They also discovered that Lewy bodies in these cells are membrane-bound and contain other organelles and membrane fragments, contradicting the previously held belief that Lewy bodies were only made up of misfolded proteins.

This is the first study to demonstrate that both alpha-synuclein and an immune response are required for Lewy body formation, and that this effect is limited to dopaminergic neurons. It also gives critical information about the formation and structure of Lewy bodies, which may be useful in future treatment development.

“Replicating Lewy body formation in living neurons is a significant step forward to understanding key aspects of Parkinson’s and other neurological disease,” says Peter McPherson, a researcher at The Neuro and the study’s senior author. “These neurons came from stem cells of healthy patients, suggesting anyone can develop Parkinson’s if exposed to the right environment, and so a genetic predisposition to disease may not be necessary.”

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

For more information: Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines, Nature Neuroscience , https://dx.doi.org/10.1038/s41593-024-01775-4