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

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

Paweł Dubiela  1   2 , Paulina Szymańska-Rożek  3 , Andrzej Eljaszewicz  1 , Patryk Lipiński  4 , Piotr Hasiński  5 , Dorota Giersz  1 , Alicja Walewska  1 , Marlena Tynecka  1 , Marcin Moniuszko  1 , Anna Tylki-Szymańska  4
Affiliations

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

Paweł Dubiela et al. Biomolecules. .

Abstract

Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for β-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 α-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 α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. α-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 α-synuclein mRNA. There was no correlation found between the level of α-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.

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

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Lyso-Gb1 concentration (ng/mL) in GD patients and GBA1 carriers compared to healthy control subjects. IQR represents the interquartile range.
Figure 2
Figure 2
Alpha synuclein mRNA level. The SNCA gene expression level among GD1 and GD3 patients was compared to that among GBA1 mutation carriers and healthy control subjects. Results are presented as the change-in-cycling-threshold using the ΔCq method.
Figure 3
Figure 3
Total α-SNCA protein level (ng/mL) among GD1 and GD3 patients compared to GBA1 mutation carriers and healthy control subjects. IQR represents the interquartile range.
Figure 4
Figure 4
Oligomer α-SNCA protein concentration (ng/mL) among GD1 and GD3 patients compared to GBA1 mutation carriers and healthy control subjects. IQR represents the interquartile range.
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