Bartels & Selkoe reply

replying to J. Burré et al. Nature498, 10.1038/nature12125 (2013) In disagreeing with our report that native α-synuclein occurs physiologically as an α-helically folded tetramer in neural and erythroid cells 1 , Burré et al . 2 conclude instead that ‘native brain α-synuclein’ consists of a largely unstructured monomer. They make two implications about our paper that are inaccurate: (1) that our findings pertained only to erythrocyte α-synuclein (we reported multiple experiments on neural cells); and (2) that we concluded that cellular α-synuclein is a stable tetramer under all conditions (we did not use the term ‘stable’, and we observed monomers and some other oligomers in normal cells (e.g., Fig. 1d of ref. 1 )). Indeed, we emphasized the need to discover “compounds that … could kinetically stabilize native tetramers and prevent pathogenic α-synuclein aggregation”. Although the data in our report suggest that tetramers are the predominant native species, tetramers and other oligomers arise from monomers, so there must be an equilibrium between monomeric and oligomeric forms in cells. Pathogenic events (e.g., mutations) could alter this equilibrium, and some therapeutic compounds could potentially re-establish it, as we explicitly suggested 1 .