Researchers have found that the structure of Parkinson's disease-associated protein aggregates can tell us, for the first time, about their movement through the brain. These new findings indicate that Parkinson's disease is a kind of amyloidosis, which has implications for its diagnosis and treatment.
Lewy bodies, primarily composed of α-synuclein proteins (α-syn), are the neuropathological hallmark of Parkinson's disease. However, we don't yet fully understand how or why they appear in the brain. Using state-of-the-art imaging techniques, researchers have found that Lewy bodies in Parkinson's disease brains contain α-syn protein aggregates (called amyloid fibrils) that can propagate through the brain. These findings, published in PNAS, support the new idea that Parkinson's disease is a kind of amyloidosis, which is a group of rare diseases caused by abnormal protein accumulation.
"Our work follows on from in vitro findings that aggregates of α-synuclein that can propagate through the brain have a cross-β structure," says lead author of the study. "Our study is the first to find that aggregates in Parkinson's disease brains also have this cross-β structure. This could mean that Parkinson's disease is a kind of amyloidosis that features the accumulation of amyloid fibrils of α-synuclein."
While immunostaining can tell us about the localization of a protein of interest, it doesn't tell us about its conformation. Electron microscopy can tell us about morphological features, but not about protein structure. Similarly, Fourier-transform infrared spectroscopy can tell us about the secondary structure of proteins, but not about their fibrillary organization.
The researchers therefore teamed up with the large-scale synchrotron radiation facility, SPring-8, and used microbeam X-ray diffraction to visualize the ultrastructure of Lewy bodies in the post mortem brain slices of three patients with Parkinson's disease. Some of the α-syn aggregates did indeed have a cross-β structure, but there was quite a bit of variety in the state of amyloid proteins.
"One possibility is that this variability could indicate the different maturity stages of Lewy bodies," says the first author of the paper. "This has obvious implications in the diagnosis of Parkinson's disease, and could also have therapeutic implications in the long run."
The researchers suggest that Parkinson's disease is a systemic (whole-body) amyloidosis rather than one that is localized to one part of the brain. This fits with the non-motor symptoms that patients experience before the onset of motor dysfunction and the multiple organ involvement of α-syn pathology. The findings from this work are highly applicable to the development of new diagnostic and therapeutic tools for the treatment of Parkinson's disease.
Synuclein aggregates in Parkinson's can move through the brain before developing into Lewy bodies
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