Deposition of α-synuclein aggregates occurs widely in the central and peripheral nervous systems in Parkinson’s disease (PD). Although recent evidence has suggested that cell-to-cell transmission of α-synuclein aggregates drives the progression of PD, the mechanism by which α-synuclein aggregates spread remains undefined. Here, we show that α-synuclein aggregates are perpetually transmitted through a continuous cycle involving uptake of external aggregates, co-aggregation with endogenous α-synuclein, and exocytosis of the co-aggregates. Moreover, we found that glucocerebrosidase depletion, which has previously been strongly associated with PD and increased cognitive impairment, promoted propagation of α-synuclein aggregates. These studies define how α-synuclein aggregates spread among neuronal cells and explain how glucocerebrosidase mutations increase the risk of developing PD and other synucleinopathies.
Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect disease phenotype. Here, we amplified α-synuclein aggregates from PD and MSA brain extracts and analyzed the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies.
A single amyloidogenic protein is implicated in multiple neurological diseases and capable of generating a number of aggregate “strains” with distinct structures. Among the amyloidogenic proteins, α-synuclein generates multiple patterns of proteinopathies in a group of diseases, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, the link between specific conformations and distinct pathologies, the key concept of the strain hypothesis, remains elusive. Here we show that in the presence of bacterial endotoxin, lipopolysaccharide (LPS), α-synuclein generated a self-renewable, structurally distinct fibril strain that consistently induced specific patterns of synucleinopathies in mice. These results suggest that amyloid fibrils with self-renewable structures cause distinct types of proteinopathies despite the identical primary structure and that exposure to exogenous pathogens may contribute to the diversity of synucleinopathies.
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