My PD Story

2025 Trailblazer Award

Rethinking Lewy Bodies and Cellular Traffic in Parkinson’s Disease

In Parkinson’s disease (PD), it is believed that dopamine neurons break down in part due to internal buildup of disruptive clumps called Lewy bodies. These Lewy bodies contain many lipids, which make up membranes of cellular components, and proteins including a misfolded form of a protein called alpha-synuclein. While much research has focused on what damage Lewy bodies cause to cells after they are formed, we still do not fully understand what causes them to form in the first place.

Wilma van de Berg, PhD, recipient of a Parkinson’s Foundation Trailblazer Award, is piecing together what conditions lead to Lewy body formation in neurons. By better understanding how Lewy bodies form, researchers can design treatments and therapies that could prevent them from forming and fight PD progression.

“Our conceptually highly innovative research can potentially transform Lewy body research and contribute to the development of complementary strategies for currently lacking disease-modifying therapies in PD.” – Dr. van de Berg

Alpha-synuclein is involved in regulating the shuttling of signaling molecules like dopamine into and out of neurons. It does so by attaching to lipid membranes of vesicles, little enclosed packages optimized for transport.

Dr. van de Berg believes that PD causes a disruption in alpha-synuclein’s shuttling role at these membranes in cells, leading to traffic jams of vesicles and other proteins that then become Lewy bodies. She also theorizes that alpha-synuclein may misfold within developing Lewy bodies, rather than misfolded alpha-synuclein causing Lewy bodies, a novel perspective.

To test this hypothesis, Dr. van de Berg, senior postdoc Dr. Tim Moors (Co-PI) and their team at the VU University Medical Center in Amsterdam, Netherlands, will first analyze postmortem brain tissue samples from people who did and did not have PD. They expect to see lower levels of critical shuttling regulation proteins in PD-affected neurons compared to non-PD neurons.

Next, Dr. van de Berg’s team will use neuron-like cells in petri dishes to see if deactivating cell shuttling signals (forcing a cellular traffic jam) leads to Lewy body formation. This could further confirm her hypothesis, especially if it leads to natural alpha-synuclein misfolding as well.

Dr. van de Berg’s team will also test a treatment involving PARP-1 inhibitors, intended to “loosen up” this traffic jam, to see if it can improve the health of those petri dish neurons with Lewy bodies. These experiments could set the foundation for future PD treatment development centered on this new understanding of Lewy body formation.

“The development of alternative and complementary hypotheses for Lewy body formation, their exploration in model systems, and their translation to patient-relevant materials are urgently needed,” said Dr. van de Berg. “I am really excited that I will be able to test our hypothesis and hope to contribute to novel therapeutics in the PD field.”

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