Deciphering Parkinson's: The Therapeutic Potential of a Novel Chaperone in Gaucher-Associated Dopaminergic Neurons

Mutations in the GBA1 gene, which is associated with Gaucher disease, are a significant genetic risk factor for Parkinson's disease. Lysosomes, as indicated by this genetic connection, are considered pivotal in Parkinson's pathogenesis. To investigate the influence of glucocerebrosidase on Parkinson's and to explore potential treatments, researchers derived induced pluripotent stem cells from Gaucher disease patients, including those with and without Parkinson's symptoms, and differentiated them into macrophages and dopaminergic neurons. These cells showed decreased glucocerebrosidase activity and an accumulation of glucosylceramide and glucosylsphingosine, mirroring Gaucher patients' conditions. Notably, neurons from patients with Type 2 and Type 1 Gaucher disease who had Parkinson's displayed a reduction in dopamine storage and dopamine transporter function. There was also an increase in α-synuclein, a protein linked to Parkinson's and related disorders, specifically in neurons from patients with Parkinson's or Type 2 Gaucher disease.

The cells were treated with NCGC607, a small-molecule chaperone for glucocerebrosidase identified through extensive screening and optimization. This treatment effectively supported the mutant enzyme, restoring its activity and protein levels, and reducing glycolipid accumulation in both macrophages and dopaminergic neurons derived from iPSCs. This suggests that NCGC607 could be a promising candidate for treating neuronopathic Gaucher disease. Furthermore, NCGC607 was found to decrease α-synuclein levels in dopaminergic neurons from Parkinson's patients, hinting at the potential utility of noninhibitory small-molecule chaperones for the treatment of Parkinson's disease.

The significance of this research lies in the creation of dopaminergic neurons from iPSCs of Gaucher patients, which showed a deficiency in enzymatic activity and elevated α-synuclein levels in those with Parkinson's. The application of a novel noninhibitory glucocerebrosidase chaperone was able to reverse these deficiencies, restore glucocerebrosidase function, and decrease glycolipid storage. Additionally, the reduction of α-synuclein levels in neurons suggests a new therapeutic approach for both Parkinson's disease and neuronopathic Gaucher disease.