The natively disordered protein alpha-synuclein is the primary component of Lewy 
bodies, the cellular hallmark of Parkinson's disease. Most studies of this 
protein are performed in dilute solution, but its biologically relevant role is 
performed in the crowded environment inside cells. We addressed the effects of 
macromolecular crowding on alpha-synuclein by combining NMR data acquired in 
living Escherichia coli with in vitro NMR data. The crowded environment in the 
E.coli periplasm prevents a conformational change that is detected at 35 degrees 
C in dilute solution. This change is associated with an increase in hydrodynamic 
radius and the formation of secondary structure in the N-terminal 100 amino acid 
residues. By preventing this temperature-induced conformational change, crowding 
in the E.coli periplasm stabilizes the disordered monomer. We obtain the same 
stabilization in vitro upon crowding alpha-synuclein with 300 g/l of bovine 
serum albumin, indicating that crowding alone is sufficient to stabilize the 
disordered, monomeric protein. Two disease-associated variants (A30P and A53T) 
behave in the same way in both dilute solution and in the E.coli periplasm. 
These data reveal the importance of approaching the effects of macromolecular 
crowding on a case-by-case basis. Additionally, our work shows that discrete 
structured protein conformations may not be achieved by alpha-synuclein inside 
cells, implicating the commonly overlooked aspect of macromolecular crowding as 
a possible factor in the etiology of Parkinson's disease.