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

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Neurotherapeutics

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.

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Acknowledgments

This work was supported by Amicus Therapeutics, Inc., the UCLA Morris K. Udall Parkinson Disease Research Center of Excellence (PHS grant NS-P50 NS38367), and gifts to the Center for the Study of Parkinson’s Disease at UCLA. We thank Dr. Alan Garfinkel, UCLA, for help with statistical analyses, and Fabrice Cordelières, CNRS France, for providing the protocol on confocal tile scan imaging. Confocal laser scanning microscopy was performed at the California NanoSystems Institute (CNSI) Advanced Light Microscopy/Spectroscopy Core Laboratory at UCLA, supported by funding from a NSF Major Research Instrumentation grant (CHE-0722519). MFC has received honoraria and travel reimbursement from the Michael J. Fox Foundation. LP, BR, RK, JF, DJL, BAW, and SWC are employees of Amicus Therapeutics. BW is the author of 2 patents that are related to this work. The authors have no additional financial interests.

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Authors and Affiliations

  1. The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA, 90095-1769, USA

    Franziska Richter, Sheila M. Fleming, Melanie Watson, Vincent Lemesre, Chunni Zhu, Farzad Mortazavi, Caitlin K. Mulligan, Pedrom C. Sioshansi, Sindalana Hean, Krystal De La Rosa & Marie-Françoise Chesselet

  2. Amicus Therapeutics, 1 Cedar Brook Drive, Cranbury, NJ, 08512, USA

    Lee Pellegrino, Brian Ranes, Richie Khanna, John Flanagan, David J. Lockhart & Sean W. Clark

  3. Amicus Therapeutics, 11099 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Brandon A. Wustman

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  1. Franziska Richter
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Correspondence to Marie-Françoise Chesselet.

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Richter, F., Fleming, S.M., Watson, M. et al. A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy. Neurotherapeutics 11, 840–856 (2014). https://doi.org/10.1007/s13311-014-0294-x

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