Parkinson’s Lewy Bodies Formed in Human Neuronal Stem Cells

Lewy bodies are a hallmark of Parkinson’s disease (PD) and other related neurological conditions. The presence of Lewy bodies in the brain is considered a “pathologic certainty” of Parkinson’s disease, but they can only be seen during an autopsy. Now, researchers at The Neuro (Montreal Neurological Institute-Hospital) of McGill University, in collaboration with its Early Drug Discovery Unit, have recreated the growth of Lewy bodies in human neurons and followed their formation to gain important insight into why and how they form. The researchers discovered immune challenge is important for this process, identifying a previously unknown link between the immune system and neurological disease.

The findings are published in Nature Neuroscience in an article titled, “Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines.”

“Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson’s disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-γ or interleukin-1β treatment) or when co-cultured with activated microglia-like cells.”

Lewy bodies are thought to result from a buildup of misfolded proteins in neurons. Previously, the only way to study them in human neurons was through brain autopsy, which is not ideal because cells break down quickly after death.

In the current study, the researchers used human stem cells to create Lewy bodies in living dopaminergic neurons, the kind of cells especially at risk in PD. The researchers did this by incubating the neurons with a protein called alpha-synuclein, which is found in Lewy bodies, and coupling it to an immune reaction.

The researchers observed that Lewy bodies develop only when dopaminergic neurons are exposed to both a rise in alpha-synuclein and an immune stimulation. Without the immune challenge, no Lewy bodies developed. Moreover, performing the same procedure on other cells, such as cortical neurons does not produce Lewy bodies, suggesting this effect is specific to dopaminergic neurons.

By following the development of Lewy bodies in real-time, the scientists discovered that in dopaminergic neurons, the immune response impairs autophagy. 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 provides important insight into Lewy body formation and structure which could be important to future drug development.

“Replicating Lewy body formation in living neurons is a significant step forward to understanding key aspects of Parkinson’s and other neurological disease,” said Peter McPherson, PhD, 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,” added Armin Bayati, a PhD 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.”