A glucocerebrosidase chaperone to ward off Parkinson’s disease

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Science Translational Medicine  10 Aug 2016:
Vol. 8, Issue 351, pp. 351ec128
DOI: 10.1126/scitranslmed.aah5492

Gaucher disease (GD) is a lysosomal storage disorder caused by deficiencies in glucocerebrosidase, which functions in glycolipid metabolism to break down glucocerebroside. Mutations in GBA1, the gene encoding glucocerebrosidase, are the most common genetic risk factor for Parkinson’s disease (PD). Recent reports that impaired glucocerebrosidase activity may promote increased levels of α-synuclein—a key mediator of PD pathogenesis—have ignited significant interest in targeting the function of this enzyme for the treatment of PD. Now, Aflaki et al. report on the beneficial effects of the noninhibitory small-molecule chaperone NCGC607 on glucocerebrosidase function in dopamine neurons. NCGC607 crosses the blood-brain barrier and therefore could prospectively be used to treat patients with, or at risk for, PD.

The authors generated induced pluripotent stem cell (iPSC) lines from patients with either type I (non-neuronopathic) or type II (neuronopathic) GD. Type I GD lines were generated from patients with or without a diagnosis of PD, allowing the authors to compare phenotypes between these two groups. Dopamine neurons derived from all GD lines exhibited reduced glucocerebrosidase protein expression and activity with concomitant increases in the levels of two of the enzyme’s substrates. These phenotypes were partially reversed by NCGC607. Neurons from patients with GD type I and PD or GD type II displayed greater loss of glucoceribrosidase activity, reduced levels of intracellular dopamine, and decreased dopamine uptake. These neurons also exhibited substantially elevated α-synuclein protein, which is blocked by NCGC607. Two GD type I patients are siblings with the same homozygous GBA1 N370S mutation, yet are discordant for PD. Elevated α-synuclein was only observed in neurons from the sibling with PD, suggesting additional factors beyond glucocerebrosidase activity are involved in regulating α-synuclein levels in dopamine neurons. NCGC607 treatment is sufficient to restore α-synuclein levels to near normal in culture, highlighting a need to characterize the effects of the compound in vivo using animal PD models. Nonetheless, the efficacy of NCGC607 in cultured human dopamine neurons is an important first step on the road to potential treatment for two diseases with possible overlapping mechanisms.

E. Aflaki et al., A new glucocerebrosidase chaperone reduces α-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and Parkinsonism. J. Neurosci. 36, 7441–7452 (2016). [Abstract]

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