title: A GCase chaperone improves motor function in a mouse model of synucleinopathy.
abstract: 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.
authors.affiliation: The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA, 90095-1769, USA.
authors.forename: Franziska
authors.initials: F
authors.lastname: Richter
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Fleming
authors.forename: Melanie
authors.initials: M
authors.lastname: Watson
authors.forename: Vincent
authors.initials: V
authors.lastname: Lemesre
authors.forename: Lee
authors.initials: L
authors.lastname: Pellegrino
authors.forename: Brian
authors.initials: B
authors.lastname: Ranes
authors.forename: Chunni
authors.initials: C
authors.lastname: Zhu
authors.forename: Farzad
authors.initials: F
authors.lastname: Mortazavi
authors.forename: Caitlin K
authors.initials: CK
authors.lastname: Mulligan
authors.forename: Pedrom C
authors.initials: PC
authors.lastname: Sioshansi
authors.forename: Sindalana
authors.initials: S
authors.lastname: Hean
authors.forename: Krystal
authors.initials: K
authors.lastname: De La Rosa
authors.forename: Richie
authors.initials: R
authors.lastname: Khanna
authors.forename: John
authors.initials: J
authors.lastname: Flanagan
authors.forename: David J
authors.initials: DJ
authors.lastname: Lockhart
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Wustman
authors.forename: Sean W
authors.initials: SW
authors.lastname: Clark
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Chesselet
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050112:Imino Pyranoses / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000201:enzymology* / Q000517:prevention & control*; D066329:Protein Aggregates / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013644:Tartrates; D051844:alpha-Synuclein / Q000378:metabolism*; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors*
chemical_list: C000599126:AT2101; D050112:Imino Pyranoses; D066329:Protein Aggregates; C497604:SNCA protein, human; D013644:Tartrates; D051844:alpha-Synuclein; C098432:isofagomine; D001617:beta-Glucosidase