Abstract
α-Synuclein (αS) deposition is a defining characteristic of Parkinson’s disease (PD) pathology, and other synucleinopathies. αS aggregates in disease, leading to the generation of neuronal inclusions known as Lewy bodies. These accumulate in the cytoplasmic space of dopaminergic neurons in the substantia nigra pars compacta region of the brain, causing cell death, resulting in decreased dopamine levels, and ultimately PD symptoms. To date, a significant proportion of structural information has arisen from in vitro studies using recombinantly purified forms of the protein, often failing to acknowledge that αS is natively located in the presence of phospholipids, where it likely plays a direct role in regulating synaptic vesicle function and neurotransmission. Here we present a series of macromolecular αS assemblies not previously described that form in the presence of lipid vesicles. These fibrillar structures are striking in both their large size relative to those previously reported and by their varying helical content, from ribbons to wave-like helices of long pitch shortening to those more compact and bulkier. These studies provide the foundation for more detailed structural analysis, and may offer new possibilities to further define disease-relevant versions of the protein that are accessible to pharmacological intervention.
Highlights
Α-Synuclein, which has been described as intrinsically disordered or helical, is capable, under certain conditions, of aggregating into a range of different amyloid fibril morphologies[1]
Using transmission EM (TEM) we report for the first time the formation of a range of large macromolecular structures that vary widely in their morphology (Fig. 1)
DMPS vesicles were chosen as a model phospholipid system since they are a key component within dopaminergic synaptic vesicles, and the negative charge on their surface has been shown to be capable of significantly promoting αS primary nucleation[15,16]
Summary
Α-Synuclein (αS), which has been described as intrinsically disordered or helical, is capable, under certain conditions, of aggregating into a range of different amyloid fibril morphologies[1]. More recent studies are emerging in which aggregates of αS from specific neurodegenerative diseases and key regions of the brain are isolated in small quantities[8,18] The latter have been used to seed recombinant forms of αS produced in bacteria or cell culture, with the assumption that seed conformation is maintained in mature fibres, without polymorphic shift, and those observed within imaging is of the diseaserelevant type. We describe very different and much larger assemblies that have not been previously reported, and which form in the presence of lipid vesicles This is interesting given the emerging discussion over whether Parkinson’s disease (PD) is a proteinopathy or lipidopathy[20]. Given the role that αS plays within the cell, that these structures could have biological or pathological relevance and far-reaching implications in defining a disease-relevant conformation towards identification of a druggable target
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