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

Biomolecules. 2023 Apr 3;13(4):644. doi: 10.3390/biom13040644.

PMID: 37189391

Paweł Dubiela, Paulina Szymańska-Rożek, Andrzej Eljaszewicz

Highlights: This is a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and α-synuclein for Gaucher disease (GD) and Parkinson's disease (PD), respectively.

Abstract

Background and objective: The most common sphingolipidosis, known as Gaucher disease (GD), is brought on by pathogenic mutations that are biallelic in the GBA1 gene, which codes for β-glucocerebrosidase (GCase, E.C. 3.2.1.45). Hepatosplenomegaly, hematological anomalies, and bone disease are the main characteristics of the disorder in both neuronopathic type 3 (GD3) and non-neuronopathic type 1 (GD1) cases. Remarkably, among GD1 patients, GBA1 variants were identified as one of the primary risk factors for the onset of Parkinson's disease (PD). A thorough investigation was conducted into the two main disease-specific biomarkers for GD and PD, respectively, glucosylsphingosine (Lyso-Gb1) and α-synuclein.

Results and conclusion: The study included 16 healthy individuals, 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients). Lyso-Gb1 was assessed by dried blood spot testing. The level of α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. Patients with GD3 and carriers of L444P were shown to have considerably higher levels of α-synuclein mRNA. The low level of α-synuclein mRNA is observed in both GD1 patients and GBA1 carriers of an unidentified or unconfirmed variation, as well as in healthy controls. Age and α-synuclein mRNA level did not correlate in GD patients receiving ERT; however, in L444P carriers, the two variables did correlate positively.

Keywords: Gaucher disease, Parkinson’s disease, enzyme replacement therapy, glucosylsphingosine, α-synuclein