Table 5.
Presentation of some genetic determinants associated with α-synuclein (α-syn) pathology and having a direct relationship with lipid pathways. This table provides some examples of different genes (first column) associated with α-syn pathology and/or to parkinsonism (second column). Mutations in these genes can directly affect the biological metabolism (third column) and, in some cases, the properties of α-syn (fourth column).
| Genes | Genetic Determinants Associated with α-Syn Pathologies | Effect on Lipids | Effects on α-Syn |
|---|---|---|---|
| ATXN2 | Diseases associated with ATXN2 include Spinocerebellar Ataxia 2 and PD/parkinsonism with LB pathology [191]. | Ataxin-2 expansion affects ceramide-sphingomyelin metabolism [192]. | NI |
| C19orf12 | C19orf12 is associated with Neurodegeneration with Brain Iron Accumulation disorders with prominent widespread Lewy body pathology [193]. | Role in lipid homeostasis [194]. | NI |
| DGKQ | DGKQ emerged as PD risk factor in independent GWAS studies [195,196] . | Controls the cellular content of diglycerides. | DGKQ loss-of-function in PD might potentially leads to enhanced transcription of SNCA [197]. |
| ELOVL7 | ELOVL7 identified in GWAS studies as PD-associated gene [198]. | FA elongase 7 plays a role in synthesis of long-chain saturated fatty acids involved as precursors of membrane lipids and lipid mediators [199]. | Defects in very long chain fatty acid synthesis enhance the toxicity of α-syn WT, A53T and E46K toxicity in a yeast model of PD. The effect on α-syn A30P is inappreciable in a yeast model of PD [75]. |
| GALC | Mutations in the GALC gene are responsible for Krabbe disease, a demyelinating disorder characterised by the presence of neuronal aggregates, in part composed of α-syn [200]. | GALC catalyses the hydrolysis of substrates including galactosylceramide (GalC) and galactosylsphingosine. In PD patients, higher levels of galactosylsphingosine were found respect to controls [201]. | Galactosylceramidase treatment improves the survival and health of KD mice, prevents the formation of α-syn in spinal neurons [200] galactosylsphingosine accelerates aggregation of α-syn in a dose-dependent manner [202]. |
| GBA | PD risk factor confirmed in GWAS studies [203,204]. | Involved in glycolipid catabolism. | The decreased GCase activity identified in CSF and blood PD patients and the consequent increase in glucosylceramide level directly correlates with increased α-syn oligomer formation. |
| PLA2G6 | PLA2G6 is causative for PARK14 in patients with autosomal recessive dystonia-parkinsonism [205]. | PLA2G6 hydrolyses the sn-2 acyl chain of glycerophospholipids in free fatty acids and lysophospholipids [206]. | Pla2g6 KO mouse neurons show early increase in α-syn/phospho α-syn level [207]. Increased expression of α-syn in cell and animal model with PLA2G6 dysfunction [207]. |
| SCARB2 | SCARB2 locus identified in GWAS studies as PD-associated gene. This gene encodes LIMP2 [208]. | LIMP2 deficiency can lead to a decrease in GCase activity and α-syn degradation [209]. | LIMP2 deficiency can lead to a decrease in GCase activity and α-syn degradation [209]. |
| SREBF1 | SREBF1 locus identified as PD risk factor in GWAS [208]. | SREBF1 encodes SREBP-1 that regulates synthesis of sterol. | NI |
| VPS13C | VPS13C first mutation identified in a form of early-onset parkinsonism; the pathological features were reminiscent of diffuse Lewy body disease [210]. | VPS13C is a lipid transport proteins [211]. | NI |
Legend. α-syn = α-synuclein, ATXN2 = Ataxin2 gene, C19orf12 = Chromosome 19 Open Reading Frame 12 gene, CSF = Cerebrospinal fluid, DGKQ = Diacylglycerol Kinase Theta gene, ELOVL7 = ELOVL Fatty Acid Elongase 7, GALC = Galactosylceramidase gene, GBA = Glucosylceramidase β gene, GWAS = genome-wide association study, KD = knockdown, KO = knockout NI = no information, PLA2G6 = Phospholipase A2 Group VI gene, SCARB2 = Scavenger Receptor Class B Member 2 gene, SREBF1 = Sterol Regulatory Element Binding Transcription Factor 1 gene, VPS13C = Vacuolar Protein Sorting 13 homolog C gene.