Shock discovery from Parkinson's research
Content of Lewy bodies; inclusions in neurons contain a membranous medley instead of the anticipated protein fibrils. [University of Basel, Biozentrum]
In a breakthrough for Parkinson's disease research, University of Basel researchers have discovered unexpected structures within the postmortem human brain tissue of a donor.
Using correlative high-resolution imaging, Professor Henning Stahlberg from Basel's Biozentrum, and colleagues, showed that inclusions in the brain's neurons were comprised of a membranous medley rather than protein fibrils.
The latest findings raises new questions about the causes of Parkinson's disease.
Parkinson's disease is one of the most common neurodegenerative diseases worldwide with hallmark neuronal inclusions - Lewy bodies - forming within the brain during the course of the disease.
But while researchers assumed that the disease is caused by deposits of insoluble fibrils consisting of the protein alpha-synculein in the Lewy bodies, new results contradict this long-held thesis.
Using correlative light and electron microscopy and tomography on brain tissue from Parkinson’s disease brain donors, Stahlberg and colleagues showed that Lewy bodies contained a crowded environment of membranes, including membrane fragments, lipids and other cellular material instead of the anticipated fibrils.
Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy while the high lipid content was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics.
"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 Stahlberg.
"The discovery that alpha-synuclein did not present in the form of fibrils was unexpected for us and the entire research field," he adds.
Currently, the researchers do not know where and in what form the protein alpha-synuclein is hidden amongst the membrane fragments and how it is involved in the formation of Lewy bodies.
However, research 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,” says Stahlberg. “Today's technologies enable us to have a much more detailed look into the morphology of human brain."
"The big question for us now is: How does alpha-synuclein contribute to the formation of Lewy bodies, if not present in form of fibrils?” he adds.
Research is published in Nature Neuroscience.