α-synuclein and lipids in erythrocytes of Gaucher disease carriers and patients before and after enzyme replacement therapy

Moraitou M, Sotiroudis G, Papagiannakis N, Ferraz MMJ, Xenakis A, Aerts JMFG, Stefanis L, and Michelakakis H. (2023) α-synuclein and lipids in erythrocytes of Gaucher disease carriers and patients before and after enzyme replacement therapy. Public Library of Science One.

Gaucher disease (GD) is a rare autosomal recessive metabolic disorder with a prevalence of 1 in 40 000 people and has been associated with over 400 different genetic mutations most often occurring in the β-glucocerebrosidase gene (GBA1). GD causes fat build up in the lysosomes of macrophages in bone marrow and a variety of organs and can affect their function. This occurs from a deficiency in β-glucocerebrosidase (GBA) activity which normally would break down these fats. People with GD often experience abdominal pain, skeletal abnormalities, and blood disorders. Interestingly, GD is a common risk factor for Parkinson’s disease (PD), a progressive neurodegenerative disease caused by an accumulation of a neuronal protein called α-synuclein (α-syn), which may be what links the two diseases. In addition to accumulated α-syn, a reduction in a unique class of phospholipids with a vinyl-ether bond at sn-1, called plasmalogens, has also been associated with both diseases. Previous work has demonstrated that the α-syn dimer/monomer ratio is positively correlated with glucosylceramide (GlcCer) and negatively associated with plasmalogens in GD. Because of this, Moraitou et al wanted to examine α-syn in red blood cell membranes and the lipidome from patients with GD, GBA1 mutation carriers (referred to as GD carriers), and GD patients on enzyme replacement therapy.

In this study there were 113 participants that were separated into 5 different groups: Group A had 45 patients with GD, Group A1 had 13 of the Group A participants before the ERT treatment, Group B had the same 13 people as Group A1 but one year after ERT, Group C consisted of 19 GD carriers, and Group D was 49 controls. When analyzing GlcCer levels in the groups, a significant increase in all species was found in the GD patients compared to the control group, however there was no difference between GD carriers and controls. As well, GD patients had reduced plasmalogen levels compared to GD carriers and control individuals, and no difference was seen between the GD carriers and the controls. When looking at α-syn, the GD patients had significant increases in monomers, dimers, and the α-syn dimer/monomer ratio compared to the GD carriers and the controls and the GD carriers α-syn dimer/monomer ratio was significantly increased compared to the control individuals.

The pre-ERT group, Group A1, was also compared against the post-ERT group, Group B, to determine if ERT could illicit an improvement in lipid or α-syn levels. After one year of treatment with ERT (Group B), a reduction in total GlcCer levels was seen compared to pre-treatment levels in Group A1 and brought to control levels although with some more variation. Group B also demonstrated a reduction in the α-syn dimer/monomer ratio and an increase in plasmalogens and nearly returning both to control levels. These results indicate that ERT was successful at augmenting levels of GlcCer, α-syn dimer/monomer ratio, and plasmalogens.

Moraitou et al were interested in looking at the relationship between α-syn and the lipidome in red blood cells of people with GD before and after ERT, GD carriers, and control individuals. People with GD were found to have increased GlcCer levels, increased α-syn dimer/monomer ratio, and reduced plasmalogens. Interestingly, this was not seen in GD carriers where the people heterozygous for GBA1 were not found to be significantly different from the control individuals in GlcCer and plasmalogen levels, but the α-syn dimer/monomer ratio was significantly increased compared to controls. This increase was not because of an increase in the α-syn monomer but because of the dimer. Moraitou et al suggest that that the GBA1 mutation could be disruptive to α-syn homeostasis resulting in increased conversion from the monomer form to the dimer form and increasing the predisposition for PD. Also, as ERT was able to recover the effect on lipids and α-syn ratio, this was the first time that some of the GD homeostatic dysregulation was shown to be reversible. Further work is necessary to determine if these effects could also occur in the brain and whether ERT would have a therapeutic effect in GD.