Saposin C protects glucocerebrosidase against α-synuclein inhibition.
Mutations in GBA1, the gene for glucocerebrosidase (GCase), are genetic risk factors for Parkinson disease (PD). α-Synuclein (α-Syn), a protein implicated in PD, interacts with GCase and efficiently inhibits enzyme activity. GCase deficiency causes the lysosomal storage disorder Gaucher disease (GD). We show that saposin C (Sap C), a protein vital for GCase activity in vivo, protects GCase against α-syn inhibition. Using nuclear magnetic resonance spectroscopy, site-specific fluorescence, and Förster energy transfer probes, Sap C was observed to displace α-syn from GCase in solution and on lipid vesicles. Our results suggest that Sap C might play a crucial role in GD-related PD.
Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, and ‡Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
Thai Leong
TL
Yap
James M
JM
Gruschus
Arash
A
Velayati
Ellen
E
Sidransky
Jennifer C
JC
Lee
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D049231:Saposins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D049231:Saposins; D051844:alpha-Synuclein; D005962:Glucosylceramidase