Objective: To find a biomarker for development of Parkinson’s disease (PD) in carriers of mutations in the glucocerebrosidase gene (GBA).

Background: Mutations in the GBA gene are the course of Gaucher disease (GD) and associated with high risk of PD development. However, not all GBA mutation carriers develop PD during their lives. Blood lysosphingolipid level, hexosylsphingosine (HexSph), (galactosylshingosine (GalSph) and glucosylsphingosine (GlcSph)) is believed now to be the most sensitive biomarker of GD [1] and is elevated in PD patients with GBA mutations (GBA-PD) [2]. If HexSph level is increased in healthy GBA mutations carriers remains unknown.

Method: We examined HexSph level in dry blood sports (DBS) in GD (N=40), GBA-PD (N=12), asymptomatic GBA mutation carriers (asymGBA) (N=19), sporadic PD (sPD) (N=89) and controls (N=74) using LS-MS/MS method [2]. HexSph level was also estimated in primary macrophage culture, derived from blood moncytes with M-CSF (Sigma-Aldrich, USA). After 5 days macrophages in concentration 2х10^6 cells/ml were put on Whatman 903® (Whatman, Germany) for LS-MS/MS analyses [3].

Results: As expected patients with GD showed marked increase in DBS HexSph level in comparison with PD patients and controls. We found increased HexSph level in the group of GBA-PD (p<0.001, p<0.001), as well as in asymGBA (p<0.001, p<0.001) in comparison with sPD and controls. There was no difference in HexSph level between GBA-PD and asymGBA.
Compared to controls HexSph concentration in macrophages were increased in asymGBA and GBA-PD patients (p<0,01, p<0,001). Surprisingly values (median (min-max), ng/ml) did not overlap between GBA-PD (45,81 (32,15-86,66)) and asymGBA (2,19 (0,83-15,32)) (p<0,001). Cut-off value was estimated as 34,6 ng/ml.

Conclusion: An assessment of HexSph level in the primary macrophage culture makes it possible to distinguish GBA mutation carriers with PD from asymptomatic mutation carriers, and though could be considered as a sensitive biomarker of PD development in carriers of GBA mutations. The study was supported with Russian Science Foundation № 19-15-00315.

References: 1. Polo G, Burlina AP, Ranieri E et al. Plasma and dried blood spot lysosphingolipids for the diagnosis of different sphingolipidoses: a comparative study. Clin Chem Lab Med. 2019; 57(12):1863-1874. 2. Pchelina S., Baydakova G., Nikolaev M. et al. Blood lysosphingolipids accumulation in patients with parkinson’s disease with glucocerebrosidase 1 mutations. Mov Disord 2018; 33: 1325-1330. 3. Nikolaev, A. E. Kopytova, G. V. Baidakova, A. K. et al., Human Peripheral Blood Macrophages as a Model for Studying Glucocerebrosidase Dysfunction. Cell and Tissue Biology 2019; 13(2):100–106.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/sensitive-biomarker-of-parkinsons-disease-linked-to-mutations-in-the-glucocerebrosidase-gene/