Saposin C protects glucocerebrosidase against α-synuclein inhibition

Biochemistry. 2013 Oct 15;52(41):7161-3. doi: 10.1021/bi401191v. Epub 2013 Oct 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Glucosylceramidase / antagonists & inhibitors
  • Glucosylceramidase / chemistry
  • Glucosylceramidase / genetics
  • Glucosylceramidase / metabolism*
  • Humans
  • Kinetics
  • Models, Molecular
  • Mutation
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Protein Binding
  • Saposins / chemistry
  • Saposins / genetics
  • Saposins / metabolism*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Enzyme Inhibitors
  • Saposins
  • alpha-Synuclein
  • Glucosylceramidase