A new glucocerebrosidase chaperone reduces α-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and parkinsonism

Elma Aflaki, Daniel K. Borger, Nima Moaven, Barbara K. Stubblefield, Steven A. Rogers, Samarjit Patnaik, Frank J. Schoenen, Wendy Westbroek, Wei Zheng, Patricia Sullivan, Hideji Fujiwara, Rohini Sidhu, Zayd M. Khaliq, Grisel J. Lopez, David S. Goldstein, Daniel S. Ory, Juan Marugan, Ellen Sidransky

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Among the known genetic risk factors for Parkinson disease, mutations inGBA1, the gene responsible for the lysosomal disorder Gaucher disease, are the most common. This genetic link has directed attention to the role of the lysosome in the pathogenesis of parkinsonism. To study how glucocerebrosidase impacts parkinsonism and to evaluate new therapeutics, we generated induced human pluripotent stem cells from four patients with Type 1 (non-neuronopathic) Gaucher disease, two with and two without parkinsonism, and one patient with Type 2 (acute neuronopathic) Gaucher disease, and differentiated them into macrophages and dopaminergic neurons. These cells exhibited decreased glucocerebrosidase activity and stored the glycolipid substrates glucosylceramide and glucosylsphingosine, demonstrating their similarity to patients with Gaucher disease. Dopaminergic neurons from patients with Type 2 and Type 1 Gaucher disease with parkinsonism had reduced dopamine storage and dopamine transporter reuptake. Levels of α-synuclein, a protein present as aggregates in Parkinson disease and related synucleinopathies, were selectively elevated in neurons from the patients with parkinsonism or Type 2 Gaucher disease. The cells were then treated with NCGC607, a small-molecule noninhibitory chaperone of glucocerebrosidase identified by high-throughput screening and medicinal chemistry structure optimization. This compound successfully chaperoned the mutant enzyme, restored glucocerebrosidase activity and protein levels, and reduced glycolipid storage in both iPSC-derived macrophages and dopaminergic neurons, indicating its potential for treating neuronopathic Gaucher disease. In addition, NCGC607 reduced α-synuclein levels in dopaminergic neurons from the patients with parkinsonism, suggesting that noninhibitory small-molecule chaperones of glucocerebrosidase may prove useful for the treatment of Parkinson disease.

Original languageEnglish
Pages (from-to)7441-7452
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number28
DOIs
StatePublished - Jul 13 2016

Keywords

  • Dopaminergic neurons
  • Glucocerebrosidase
  • Induced pluripotent stem cells
  • Parkinsonism
  • Pharmacological chaperone
  • α-synuclein

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    Aflaki, E., Borger, D. K., Moaven, N., Stubblefield, B. K., Rogers, S. A., Patnaik, S., Schoenen, F. J., Westbroek, W., Zheng, W., Sullivan, P., Fujiwara, H., Sidhu, R., Khaliq, Z. M., Lopez, G. J., Goldstein, D. S., Ory, D. S., Marugan, J., & Sidransky, E. (2016). A new glucocerebrosidase chaperone reduces α-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and parkinsonism. Journal of Neuroscience, 36(28), 7441-7452. https://doi.org/10.1523/JNEUROSCI.0636-16.2016