A GCase chaperone improves motor function in a mouse model of synucleinopathy.

ABSTRACT: Mutation of the lysosomal hydrolase acid-?-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes ?-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 ?-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 ?-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small ?-synuclein aggregates, while increasing the number of large ?-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.

SUBMITTER: Richter F 

PROVIDER: S-EPMC4391384 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature