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. 2021 May 21;26(11):3078.
doi: 10.3390/molecules26113078.

Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern

Irina A Guschina  1 , Natalia Ninkina  1   2 , Andrei Roman  1   2 , Mikhail V Pokrovskiy  3 , Vladimir L Buchman  1   2
Affiliations

Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern

Irina A Guschina et al. Molecules. .

Abstract

Recent studies have implicated synucleins in several reactions during the biosynthesis of lipids and fatty acids in addition to their recognised role in membrane lipid binding and synaptic functions. These are among aspects of decreased synuclein functions that are still poorly acknowledged especially in regard to pathogenesis in Parkinson's disease. Here, we aimed to add to existing knowledge of synuclein deficiency (i.e., the lack of all three family members), with respect to changes in fatty acids and lipids in plasma, liver, and two brain regions in triple synuclein-knockout (TKO) mice. We describe changes of long-chain polyunsaturated fatty acids (LCPUFA) and palmitic acid in liver and plasma, reduced triacylglycerol (TAG) accumulation in liver and non-esterified fatty acids in plasma of synuclein free mice. In midbrain, we observed counterbalanced changes in the relative concentrations of phosphatidylcholine (PC) and cerebrosides (CER). We also recorded a notable reduction in ethanolamine plasmalogens in the midbrain of synuclein free mice, which is an important finding since the abnormal ether lipid metabolism usually associated with neurological disorders. In summary, our data demonstrates that synuclein deficiency results in alterations of the PUFA synthesis, storage lipid accumulation in the liver, and the reduction of plasmalogens and CER, those polar lipids which are principal compounds of lipid rafts in many tissues. An ablation of all three synuclein family members causes more profound changes in lipid metabolism than changes previously shown to be associated with γ-synuclein deficiency alone. Possible mechanisms by which synuclein deficiency may govern the reported modifications of lipid metabolism in TKO mice are proposed and discussed.

Keywords: fatty acids; non-polar lipids; phospholipids; synucleins; triple-knockout mouse model.

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Conflict of interest statement

The authors declared none to disclose regarding conflict of interest.

Figures

Figure 1
Figure 1
Total lipid content in liver (mg of fatty acids in 100 mg of tissue) and plasma (mg of fatty acids in 100 µL of plasma) from wild-type (WT) and triple-synuclein null mutant (TKO) mice. Means ± s.d. (n = 6) are shown. * p < 0.05.
Figure 2
Figure 2
The relative concentrations (% of total) of the major lipid classes in liver (A) and plasma (B) from wild-type (WT) and triple-synuclein knockout mice: the total polar lipids (TPL), triacylglycerols (TAG), steryl esters (SE), and free (non-esterified) fatty acids (FFA). Values represent means ± s.d. (n = 6). * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Comparison of free (non-esterified) fatty acids (FFA) in the plasma from wild-type (WT) and triple-synuclein knockout mice (% of total FFA). Values represent means ± s.d. (n = 6). ** p < 0.01.
Figure 4
Figure 4
Fatty acid composition in individual polar lipid classes (% of total PL fatty acids) from the liver of wild-type (WT) and triple-synuclein null mutant (TKO) mice. Means ± s.d. (n = 6) are shown. Fatty acids are indicated with the number before the colon showing the number of carbon atoms, the figure afterwards denoting the number of double bonds. The position of the first double bond is shown after “n”. Only the major fatty acids (≥0.5%) are present. The asterisk (*) indicates a significant effect of triple-synuclein deficiency when compared with WT (p < 0.05).
Figure 4
Figure 4
Fatty acid composition in individual polar lipid classes (% of total PL fatty acids) from the liver of wild-type (WT) and triple-synuclein null mutant (TKO) mice. Means ± s.d. (n = 6) are shown. Fatty acids are indicated with the number before the colon showing the number of carbon atoms, the figure afterwards denoting the number of double bonds. The position of the first double bond is shown after “n”. Only the major fatty acids (≥0.5%) are present. The asterisk (*) indicates a significant effect of triple-synuclein deficiency when compared with WT (p < 0.05).
Figure 5
Figure 5
Midbrain and cortex polar lipid composition (% of total polar lipids) from wild-type (WT) and triple-synuclein null mutant (TKO) mice. Means ± s.d. (n = 5 for WT cortex; n = 6 for WT midbrain and both regions of TKO) are shown. * p < 0.05. Abbreviations: PI, phosphatidylinositol; PS, phosphatidylserine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; CL, cardiolipin; SM, sphingomyelin; SL, sulfatide; CER, cerebroside.
Figure 6
Figure 6
Fatty acid and dimethylacetal (DMA) composition in the individual polar lipid classes (% of total PL fatty acids) from the midbrain and cortex of wild-type (WT) and triple-synuclein null mutant (TKO) mice. For sulfatides and cerebrosides, the conventional (non-hydroxylated) fatty acids are present. Means ± s.d. (n = 6) are shown. Fatty acids are indicated with the number before the colon showing the number of carbon atoms, the figure afterwards denoting the number of double bonds. The position of the first double bond is shown after “n”. Only the major fatty acids (≥0.5%) are present. The asterisk (*) indicates a significant effect of triple-synuclein deficiency when compared with WT (p < 0.05).
Figure 6
Figure 6
Fatty acid and dimethylacetal (DMA) composition in the individual polar lipid classes (% of total PL fatty acids) from the midbrain and cortex of wild-type (WT) and triple-synuclein null mutant (TKO) mice. For sulfatides and cerebrosides, the conventional (non-hydroxylated) fatty acids are present. Means ± s.d. (n = 6) are shown. Fatty acids are indicated with the number before the colon showing the number of carbon atoms, the figure afterwards denoting the number of double bonds. The position of the first double bond is shown after “n”. Only the major fatty acids (≥0.5%) are present. The asterisk (*) indicates a significant effect of triple-synuclein deficiency when compared with WT (p < 0.05).
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