The article by Tim Bartels, Joanna G. Choi, and Dennis J. Selkoe challenges the widely accepted notion that α-synuclein (αSyn) is natively unfolded and proposes that it exists as a helically folded tetramer under physiological conditions. The authors used various methods, including native gel electrophoresis, scanning transmission electron microscopy (STEM), and in vivo cell crosslinking, to demonstrate that endogenous αSyn in neuronal and non-neuronal cell lines, brain tissue, and living human cells primarily forms a ~58 kDa tetramer. This tetramer exhibits α-helical structure without lipid addition and has a higher lipid binding capacity compared to recombinant αSyn. Unlike recombinant monomers, which readily aggregate into amyloid-like fibrils, native human tetramers show little to no amyloid-like aggregation. The authors suggest that destabilization of the helically folded tetramer precedes αSyn misfolding and aggregation in Parkinson's disease (PD) and other synucleinopathies. They propose that small molecules that stabilize the physiological tetramer could reduce αSyn pathogenicity, potentially offering a novel therapeutic approach for PD and related disorders.The article by Tim Bartels, Joanna G. Choi, and Dennis J. Selkoe challenges the widely accepted notion that α-synuclein (αSyn) is natively unfolded and proposes that it exists as a helically folded tetramer under physiological conditions. The authors used various methods, including native gel electrophoresis, scanning transmission electron microscopy (STEM), and in vivo cell crosslinking, to demonstrate that endogenous αSyn in neuronal and non-neuronal cell lines, brain tissue, and living human cells primarily forms a ~58 kDa tetramer. This tetramer exhibits α-helical structure without lipid addition and has a higher lipid binding capacity compared to recombinant αSyn. Unlike recombinant monomers, which readily aggregate into amyloid-like fibrils, native human tetramers show little to no amyloid-like aggregation. The authors suggest that destabilization of the helically folded tetramer precedes αSyn misfolding and aggregation in Parkinson's disease (PD) and other synucleinopathies. They propose that small molecules that stabilize the physiological tetramer could reduce αSyn pathogenicity, potentially offering a novel therapeutic approach for PD and related disorders.