Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein
Nunilo Cremades, Samuel I.A. Cohen, Emma Deas, Andrey Y. Abramov, Allen Y. Chen, Angel Orte, Massimo Sandal, Richard W. Clarke, Paul Dunne, Francesco A. Aprile, Carlos W. Bertoncini, Nicholas W. Wood, Tuomas P.J. Knowles, Christopher M. Dobson, David Klenerman
Cell, Volume 149, Issue 5, 1048-1059, 25 May 2012
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Neurodegenerative diseases share a common feature: the accumulation of abnormally aggregated proteins in pathological inclusions. Accumulating evidence suggests that soluble oligomeric species generated en route to the formation of amyloid fibrils are the most neurotoxic species linked with the development of these types of disease; however very little is known about these species, largely due to the lack of suitable tools to characterise their behaviour. We have recently develop a series of single-molecule fluorescence approaches, which, in combination with other biophysical and biochemical techniques, have allowed us to investigate in unprecedented detail the early stages of aggregation and fibril formation by a-synuclein, whose aggregation and deposition is the hallmark of Parkinson’s disease. We have been able to distinguish two distinct types of soluble protein oligomers, which can be differentiated by their kinetics of formation, their susceptibility to degradation by proteases and, importantly, by the pathophysiological effects they induce in rat primary midbrain neuronal cells when added to the culture medium, one type being benign while the other type induces the formation of massive amounts of reactive oxygen species. Our findings provide a link between two of the hallmarks associated with Parkinson’s disease: alpha-synuclein misfolding and aggregation, and oxidative stress, and the methodology developed represents a unique platform to investigate the toxic species and unravel the specific mechanisms that give rise to cellular damage in this type of diseases.
Summary contributed by the first author of the paper, Nunilo Cremades.