Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of α-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40-69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased α-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.

Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications

“…In both PD and MSA models, genes related to the regulation of lipid metabolism were affected upon SNCA overexpression. These data support the role of α-synuclein (of either neuronal or oligodendroglial origin) in the modulation of brain lipid turn-over as shown in human PD [ 79 ; 80 ] and MSA [ 62 ]. Finally, regulation of apoptosis (GO:0042981) was significantly associated with the disease processes in the striatum of both PD and MSA mice.…”

“…Of note, genes with links to lipid metabolism, such as Pdk4 (Pyruvate Dehydrogenase Kinase, Isozyme 4), Lpl (Lipoprotein Lipase) or Pla2g4e (Phospholipase A2, Group IVE) were strongly represented in this group ( Fig 7B ). Changes in lipid metabolism have been shown to be relevant to the human disease [ 62 ], and it is therefore intriguing to see that early alterations in this process might be caused by miRNA-mRNA network interactions. The module “Transmembrane transport” was a further category with prominent predicted interaction between dysregulated miRNAs and mRNAs.…”

“…Furthermore, indications of dysregulated oligodendroglial function, protein handling, transmembrane transport and metabolism, as well as switch in cell death mechanisms downstream of α-synuclein accumulation in oligodendroglia were evident in the striatum. All these processes and pathways have previously been implicated in MSA pathogenesis based on either neuropathological findings or experimental studies in later symptomatic stages of the disease [ 1 ; 2 ; 59 ; 60 ; 62 ; 63 ; 71 – 73 ].…”

“…Direct overexpression of the α-synuclein gene in oligodendroglia of the MSA transgenic mice has been shown to trigger early oligodendroglial dysfunction related to disrupted myelination and changes in oligodendroglial differentiation relevant to the human disease [ 62 ; 63 ]. It is interesting to note, however, that with the stringent correlation analysis of putative miRNA-mRNA interactions, we did not obtain evidence for a significant involvement of miRNAs on the modulation of genes linked to oligodendroglial dysfunction.…”

Animal modeling an oligodendrogliopathy – multiple system atrophy

“…Changes to microRNA-96 resulted in downregulation of the solute carrier protein family SLC1A1 and SLC6A6 [ 23 ]. Myelin instability is regarded as an early event in MSA pathogenesis and a recent study showed that the myelin lipids (sphingomyelin, sulfatide and galactosylceramide) were severely decreased in MSA white matter specifically in disease-affected regions, providing further clues to MSA pathogenesis [ 24 , 25 ].…”