Scientists have successfully replicated the development of Lewy bodies in human neurons and investigated their formation, providing valuable insights into their origins. Importantly, they discovered that immune system activation plays a crucial role in this process, unveiling a new connection between immunity and neurological disorders.
Lewy bodies are characteristic features of Parkinson’s disease (PD) and other related neurological disorders. Understanding their formation is vital for improving treatment options. Researchers at The Neuro (Montreal Neurological Institute-Hospital) in partnership with the Early Drug Discovery Unit at McGill University have recreated the growth of Lewy bodies in human neurons and studied their formation, revealing critical insights into their development. They found that the activation of the immune system is essential for this process, establishing a previously unnoticed link between the immune response and neurological diseases.
Lewy bodies are believed to form due to the accumulation of misfolded proteins within neurons. Historically, studying Lewy bodies in human neurons was limited to brain autopsies, which is not optimal as cells deteriorate rapidly post-mortem. In this research, neuroscientists employed human stem cells to generate Lewy bodies in living dopaminergic neurons, the type of cells particularly vulnerable in PD.
The researchers achieved this by exposing the neurons to a protein called alpha-synuclein, which is present in Lewy bodies, while also triggering an immune response.
The findings indicate that Lewy bodies only form when dopaminergic neurons encounter both an increase in alpha-synuclein and an immune activation. Without this immune trigger, no Lewy bodies appeared. Furthermore, replicating the same method on other cell types, like cortical neurons, did not result in Lewy body formation, suggesting that this phenomenon is exclusive to dopaminergic neurons.
By monitoring Lewy body development in real-time, the researchers found that the immune response hinders autophagy in dopaminergic neurons, a process crucial for clearing damaged cellular components. They also discovered that Lewy bodies are encased in membranes and incorporate various organelles and membrane fragments, challenging the prior belief that Lewy bodies consisted solely of misfolded proteins.
This research is the first to demonstrate that both alpha-synuclein and an immune response are necessary for the formation of Lewy bodies, highlighting that this interaction is specific to dopaminergic neurons. The insights gained could be significant for future drug development targeting Lewy body formation and structure.
“Reproducing Lewy body development in living neurons marks a notable advancement in our understanding of critical aspects of Parkinson’s and other neurological disorders,” explains Peter McPherson, a researcher at The Neuro and the study’s lead author. “These neurons originated from healthy patients’ stem cells, suggesting that anyone could potentially develop Parkinson’s if exposed to certain environmental factors, indicating that a genetic predisposition might not be required.”
“The findings reinforce earlier studies that indicate an immune response plays a significant role in the progression of Parkinson’s,” states Armin Bayati, a PhD candidate in McPherson’s lab and the study’s first author. “Future research should delve into how inflammation due to an overactive immune system contributes to Lewy body formation when combined with α-synuclein.”
The results of this research were published in the journal Nature Neuroscience on October 8, 2024. The study received support from the Canada First Research Excellence Fund, Healthy Brain, Healthy Lives, the Canadian Institutes for Health Research, and Fonds de recherche du Québec-Santé.
