A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy

Neurotherapeutics. 2014 Oct;11(4):840-56. doi: 10.1007/s13311-014-0294-x.


Mutation of the lysosomal hydrolase acid-β-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes α-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type α-synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced α-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small α-synuclein aggregates, while increasing the number of large α-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations.

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / enzymology*
  • Brain / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Humans
  • Imino Pyranoses / pharmacology
  • Male
  • Mice
  • Motor Activity / drug effects
  • Parkinson Disease / enzymology*
  • Parkinson Disease / prevention & control*
  • Protein Aggregates / drug effects
  • Protein Transport / drug effects
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Tartrates
  • alpha-Synuclein / metabolism*
  • beta-Glucosidase / antagonists & inhibitors*


  • AT2101
  • Imino Pyranoses
  • Protein Aggregates
  • SNCA protein, human
  • Tartrates
  • alpha-Synuclein
  • isofagomine
  • beta-Glucosidase