Alpha-synuclein is an intensely studied intrinsically disordered protein whose aggregation into amyloid fibrils is connected to the progression of several neurodegenerative diseases, most commonly Parkinson’s Disease. A remarkable feature that has emerged from this research is how easy it is to induce the protein to aggregate in vitro into a wide range of amyloid fibrils that appear to resemble the aggregates found in Lewy bodies in diseases like Parkinson’s while at the same time how difficult it is to produce aggregates whose fold truly represents the disease-associated amyloids at the atomic level. In an effort to produce the disease-relevant fibrils in vitro we have analyzed over 60 independent samples by cryo-electron microscopy using helical reconstruction to obtain atomic resolution models for most of the samples. While not yet achieving our original goal, we have found that several overlooked parameters influence the structural outcomes of alpha-synuclein aggregation, in particular protein purity, preparation of the monomeric starting material and agitation method.
Heterotypic interactions with Aβ42 reshape α-syn aggregation pathways and fibril conformations, generating structurally distinct α-syn fibril populations with different neuronal seeding activities, which provide a molecular framework for understanding how cross-talk between amyloidogenic proteins may contribute to stru...
Purnopama Saha, Teshani Liyanaarachchige, Anika Alim et al.· bioRxiv· 0 citations
The aggregation of proteins into fibrillar amyloids is central to the pathology of neurodegenerative disorders. However, the relationship between the structure of amyloid aggregates and disease progression remains incompletely understood, in part because amyloid systems are intrinsically heterogeneous: structurally dis...
D. Baghel, Ayanjeet Ghosh· Accounts of Chemical Researc...· 0 citations
Amyloid fibrils are implicated in a myriad of human diseases. A striking observation is that fibrils extracted from diseased tissues are characterized by a restricted set of folds unique to the specific pathology. In contrast, fibrils grown in vitro exhibit extensive structural diversity, suggesting that specific envir...
Mikołaj I Kuska, Łucja Kozicka, S. Prodhan et al.· bioRxiv· 0 citations
It is shown that oligomerization drives a transition from dynamic monomers to increasingly ordered intermediates, relevant to models in which α-syn oligomerization alters normal membrane engagement during PD-associated aggregation.
Raya Sadighi, Andrea Istrati, Sigourney Karijodikoro et al.· ACS Central Science· 1 citation
The non-amyloid-β component (NAC) region of the Parkinson’s-associated protein α-synuclein plays a key role in its pathogenic aggregation, motivating the development of molecules that target this critical region. Here, we show that a minimal NAC-derived motif, 66VGGAVVT72, can be reprogrammed through backbone engineeri...
Haoliang Zheng, Kyren Miller, Magdalena I. Ivanova et al.· bioRxiv· 0 citations
It is shown that JB6 binds to Aβ42 fibrils with high affinity and that this binding can quantitatively explain the observed elongation inhibition, offering a mechanistic link between chaperone–fibril binding and amyloid suppression.
Andreas Carlsson, U. Olsson, S. Linse· bioRxiv· 0 citations
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