Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons
Buell, Alexander K
Laine, Romain F
Kaminski, Schierle Gabriele S
Proceedings of the National Academy of Sciences
National Academy of Sciences
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Pinotsi, D., Michel, C., Buell, A. K., Laine, R. F., Mahou, P., Dobson, C., Kaminski, C., & et al. (2016). Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons. Proceedings of the National Academy of Sciences, 113 3815-3819. https://doi.org/10.1073/pnas.1516546113
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.
optical nanoscopy, seeding, neurodegenerative disease, prion-like behaviour, α-synuclein
We thank Dr Q. Jeng and Dr A. Stephens for technical assistance and Dr J. Skepper for TEM imaging. This work was funded by grants from the U.K. Medical Research Council (MR/K015850/1 and MR/K02292X/1), Alzheimer’s Research UK (ARUK-EG2012A-1), U.K. Engineering and Physical Sciences Research Council (EPSRC) (EP/H018301/1) and the Wellcome Trust (089703/Z/09/Z). D.P. wishes to acknowledge support from the Swiss National Science Foundation and the Wellcome Trust through personal fellowships. A.K.B thanks Magdalene College, Cambridge and the Leverhulme Trust for support.
Wellcome Trust (089703/Z/09/Z)
External DOI: https://doi.org/10.1073/pnas.1516546113
This record's URL: https://www.repository.cam.ac.uk/handle/1810/254408