Abstract
Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD.
Highlights
Protein misfolding and aberrant aggregation processes that elude cellular maintenance mechanisms can result in major disturbances of cellular processes
No aggregation of α-syn was detected during the time frame of the experiment in the PEGylated plates, whereas reproducible kinetic traces with typical sigmodal curves were observed in PS plates (S3A)
Another striking observation from the current experiments in PS plates is that α-syn aggregation kinetics appear independent of the peptide concentration at high monomer concentrations
Summary
Protein misfolding and aberrant aggregation processes that elude cellular maintenance mechanisms can result in major disturbances of cellular processes. This may lead to protein aggregation diseases, for example Parkinson’s disease (PD), the prevalence of which is increasing (Dobson, 2003). In PD, the formation and deposition of amyloid fibrils by the protein α-synuclein (α-syn) is the pathological hallmark associated with degeneration of dopaminergic neurons in the substantia nigra (Fink, 2006), and other brain regions. Neurodegeneration is believed to initiate at α-Syn is a natively unfolded 140 amino acid protein that exists abundantly in neuronal cells, where it is located in the proximity of vesicles within the presynaptic terminals (Izawa et al 2012).
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