α-synuclein dimerization in erythrocytes of Gaucher disease patients: correlation with lipid abnormalities and oxidative stress.

Moraitou M, Dermentzaki G, Dimitriou E, Monopolis I, Dekker N, Aerts H, Stefanis L, and Michelakakis H. (2016). α-synuclein dimerization in erythrocytes of Gaucher disease patients: correlation with lipid abnormalities and oxidative stress. Neuroscience Letters, 613: 1-5.

Gaucher disease (GD) is a rare autosomal recessive metabolic disorder that causes fat to build up in the lysosome of macrophages in bone marrow and many organs due to deficient β-glucocerebrosidase (GBA) activity. GD affects up to 1 in 40 000 people in the population and over 400 different genetic mutations have been associated with the disease. GD is also one of the most common risk factors for Parkinson’s disease (PD), a progressive neurodegenerative disease. PD has a prevalence of 1 in 500 in Canada’s population* and causes slow movement, tremors, and rigidity, as well as a range of non-motor symptoms including depression, dementia, insomnia, and bladder dysfunction. Alpha-synuclein (α-syn) is a neuronal protein involved in the pathology of PD and may be the factor linking GD to PD. In addition to α-syn, plasmalogen deficiency has been associated with both GD and PD. Moraitou et al examined the role of plasmalogens in GD using red blood cells (RBCs) of GD patients and healthy controls, chosen because α-syn is found highly expressed in these cells. This was accomplished by studying the ratio of dimer/monomer α-syn, as well as confirming oxidative stress and plasmalogen levels which were published in their previous article (1).

One of the factors involved in α-syn aggregation is oxidative stress, it was analyzed by determining levels of malonyldialdehyde (MDA), a product of lipid peroxidation. Oxidative stress is thought to induce α-syn aggregation by causing free radical damage to lipids in cellular membranes, resulting in neuronal damage. MDA levels in the GD patients were found to be significantly higher with a range of 0.7-10.6 nmol/10^10 cells compared to controls at 1.1-5.4 nmol/10^10 cells, indicating an increase in oxidative stress in the GD patients due to more lipid peroxidation. It was found that GD patients also had a significant decrease in median level of plasmalogens (measured as dimethylacetals (DMA)) relative to the corresponding phosphatidyls in the RBC membrane. This was demonstrated by a decrease in the ratio of C16:0 DMA/C16:0 by 13% and C18:0 DMA/C18:0 by 26% when compared to the healthy controls. Plasmalogens are known antioxidants and thus this decrease would have an influence on the antioxidant capacity of the membrane.

Although monomeric α-syn is a common cytosolic protein and is not pathologic, when it begins to aggregate it can form fibrils which damage cells and lead to neurodegenerative disorders. When analyzing the level of α-syn aggregation, the ratio between dimer to monomer α-syn is evaluated. Although no difference was seen in the levels of monomer α-syn between GD patients and controls, it was found that the GD patients had significantly higher levels of dimerized α-syn with a range of 0.15 to 8.02 compared to the controls at 0.01 to 2.09, indicating more aggregation. 

Taken together, plasmalogen deficiency may contribute to the link between GD and PD. Moraitou et al have provided evidence for the role of plasmalogens in GD by displaying the relationship between dimerization of α-syn and altered lipid levels, as well as increased oxidative stress. It was proposed that the reduction in plasmalogen levels contributed to an increase in oxidative stress, which further influenced α-syn aggregation. These findings are also relevant for PD, where α-syn is known to be a major component in its pathology. Plasmalogen deficiency has also been reported in PD patients and may contribute to aggregation of this toxic protein, which is able to bind to membrane lipids and interfere with membrane composition and stability, further perpetuating this neurodegenerative cycle. Moraitou et al propose that additional studies including more participants and tissues studied, especially the brain, would provide insight into the mechanisms behind plasmalogens and oxidative stress and how this influences α-syn aggregation in these diseases.

UCB Canada. https://www.ucb-canada.ca/en/Patients/Conditions/Parkinson-s-Disease

1)Moraitou M, Dimitriou E, Dekker N, Monopolic I, Aerts J, and Michelakakis H. (2014) Gaucher disease: Plasmalogen levels in relation to primary lipid abnormalities and oxidative stress. Blood, Cells, Molecules and Diseases, 53: 30-33.