Alpha-Synuclein mRNA Level Found Dependent on L444P Variant in Carriers and Gaucher Disease Patients on Enzyme Replacement Therapy

Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for beta-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson's disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and alpha-synuclein for GD and PD, respectively. A total of 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients), 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 16 healthy subjects were involved in the study. Lyso-Gb1 was assessed by dried blood spot testing. The level of alpha-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. alpha-synuclein mRNA level was found significantly elevated in GD3 patients and L444P carriers. GD1 patients, along with GBA1 carriers of an unknown or unconfirmed variant, as well as healthy controls, have the same low level of alpha-synuclein mRNA. There was no correlation found between the level of alpha-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.

Automated summary

Gaucher disease, caused by GBA1 gene variants, is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease. GBA1 variants are also important risk factors for Parkinson's disease. A study investigated biomarkers for Gaucher disease and Parkinson's disease in patients receiving enzyme replacement therapy (ERT). The results showed elevated levels of alpha-synuclein mRNA in GD3 patients and L444P carriers, while GD1 patients, GBA1 carriers with unknown variants, and healthy controls had low levels of alpha-synuclein mRNA. The level of alpha-synuclein mRNA did not correlate with age in GD patients treated with ERT, except for L444P carriers.