Erschienen in:
01.10.2014 | Original Article
A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy
verfasst von:
Franziska Richter, Sheila M. Fleming, Melanie Watson, Vincent Lemesre, Lee Pellegrino, Brian Ranes, Chunni Zhu, Farzad Mortazavi, Caitlin K. Mulligan, Pedrom C. Sioshansi, Sindalana Hean, Krystal De La Rosa, Richie Khanna, John Flanagan, David J. Lockhart, Brandon A. Wustman, Sean W. Clark, Marie-Françoise Chesselet
Erschienen in:
Neurotherapeutics
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Ausgabe 4/2014
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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.