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Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons

Pinotsi D, Michel CH, Buell AK, Laine RF, Mahou P, Dobson CM, Kaminski CF, Kaminski Schierle GS, "Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons" PNAS (2016), 113 (14), pp 3815-3819.

pdf | DOI: 10.1073/pnas.1516546113


Abstract

New strategies for visualizing self-assembly at the nanoscale level are prone to grant deep insights into the function and dysfunction of molecular machineries in cells and living organisms. Of particular interest is the self-assembly of misfolded proteins into amyloid fibrils, which is related to a range of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Here, we probe the links between the mechanism of α-synuclein aggregation and its associated neuronal toxicity by using optical nanoscopy directly in a neuronal cell culture model of Parkinson’s disease. The nanoscale level of detail revealed by super-resolution microscopy enables us to show that amyloid fibrils of the protein are taken up by neuronal cells and act as seeds for elongation reactions which both consume endogenous α-synuclein and suppress its de novo aggregation. When α-synuclein is internalized in its monomeric form, however, it nucleates and triggers the aggregation of endogenous α-synuclein, leading to apoptosis, although there are no detectable cross-reactions between externally added and endogenous protein species. Monomer-induced apoptosis can be reduced by pre-treatment with seed fibrils, suggesting that partial consumption of the externally added or excess soluble α-synuclein can be significantly neuroprotective.