A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers

Summary

Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.

Highlights

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  A neuronal model recapitulates biochemical abnormalities in GBA1 mutation PD

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  Ambroxol rescued the autophagic defects in human GBA1 mutant neuronal cells

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  Ambroxol decreased α-synuclein levels human GBA1 mutant neuronal cells

Abstract

Schapira and colleagues devised a dopaminergic neuronal model from human adipose NCSCs which provided insights into the role of glucocerebrosidase dysfunction in PD pathogenesis. Glucocerebrosidase function enhancement reversed biochemical abnormalities in GBA1 mutant neurons. This method provides a platform to test potential therapeutic compounds for PD treatment.