The presynaptic protein α-synuclein (α-syn), particularly in its amyloid form, 
is widely recognized for its involvement in Parkinson disease (PD). Recent 
genetic studies reveal that mutations in the gene GBA are the most widespread 
genetic risk factor for parkinsonism identified to date. GBA encodes for 
glucocerebrosidase (GCase), the enzyme deficient in the lysosomal storage 
disorder, Gaucher disease (GD). In this work, we investigated the possibility of 
a physical linkage between α-syn and GCase, examining both wild type and the 
GD-related N370S mutant enzyme. Using fluorescence and nuclear magnetic 
resonance spectroscopy, we determined that α-syn and GCase interact selectively 
under lysosomal solution conditions (pH 5.5) and mapped the interaction site to 
the α-syn C-terminal residues, 118-137. This α-syn-GCase complex does not form 
at pH 7.4 and is stabilized by electrostatics, with dissociation constants 
ranging from 1.2 to 22 μm in the presence of 25 to 100 mm NaCl. Intriguingly, 
the N370S mutant form of GCase has a reduced affinity for α-syn, as does the 
inhibitor conduritol-β-epoxide-bound enzyme. Immunoprecipitation and 
immunofluorescence studies verified this interaction in human tissue and 
neuronal cell culture, respectively. Although our data do not preclude 
protein-protein interactions in other cellular milieux, we suggest that the 
α-syn-GCase association is favored in the lysosome, and that this noncovalent 
interaction provides the groundwork to explore molecular mechanisms linking PD 
with mutant GBA alleles.