New research challenges the conventional understanding of the cause of Parkinson’s disease. The paper, published this week in Nature Neuroscience, shows that the inclusions in the brain’s neurons, characteristic of Parkinson’s disease, are comprised of a membranous medley rather than protein fibrils.
Parkinson’s disease is one of the most common neurodegenerative diseases worldwide. This disease is typically accompanied by motor defects such as the tremor of arms and legs, slowness of movements, and muscle rigidity, which occur together with other non-motor symptoms. A characteristic of this progressively worsening and currently unstoppable disease are neuronal inclusions called Lewy bodies that occur in many regions of the brain throughout the course of the disease.
For decades, Parkinson’s disease was thought to be caused by deposits of insoluble fibrils consisting of the protein alpha-synculein in the Lewy bodies. But in their current study, the researchers refute this long-held assumption. Using state-of-the-art electron microscopes, they have shown that the Lewy bodies contain mainly membrane fragments, lipids, and other cellular material instead of the anticipated fibrils.
“We used correlative light and electron microscopy and other advanced light microscopy methods to take a closer look at the brain of deceased Parkinson’s patients and discovered that the Lewy bodies consist mainly of membrane fragments from mitochondria and other organelles, but have in most cases no or only negligible quantities of protein fibrils,” says coauthor Henning Stahlberg from the University of Basel. “The discovery that alpha-synuclein did not present in the form of fibrils was unexpected for us and the entire research field.”
Currently, the researchers do not know where and in what form the protein alpha-synuclein is hidden amongst the membrane fragments or how it is involved in the formation of Lewy bodies. However, the work indicates that the laboratory-based model of alpha-synuclein fibrils as a cause and mechanism of Parkinson’s disease should be revisited.
“The questions why it has taken so long to better characterize Lewy bodies can perhaps be answered with the previous sample preparation and electron microscopy methods. Today’s technologies enable us to have a much more detailed look into the morphology of human brain,” Stahlberg explains. “The big question for us now is this: How does alpha-synuclein contribute to the formation of Lewy bodies if not present in the form of fibrils?”
Image: Content of Lewy bodies: The inclusions in the neurons contain mainly a membranous medley instead of the anticipated protein fibrils. Image courtesy of the University of Basel, Biozentrum.