Alpha-Synuclein And Schwann Cell Differentiation: A Potential Crosstalk With Lipid Metabolism?

Abstract

Alpha-synuclein (aS) is a moonlighting protein involved in multiple cellular events. This protein has been intensively studied in central nervous system (CNS) neurons in relationship to the pathogenicity of Parkinson´s disease (PD). Curiously, aS is also expressed in the peripheral nervous system (PNS) specifically in the cytoplasm of myelinating glial cells or Schwann cells (SCs). In fact, the localization of the aS protein in the normal and parkinsonian PNS follows a pattern similar to the one of S100β, a ubiquitous mature SC-specific marker. However, the role of aS in SCs is not known. Therefore, we took advantage of available RNAseq datasets from human nerve tissues and cultured purified SCs to investigate the relationship between aS expression and SC differentiation. Intriguingly, purified human and rat SCs induced to differentiate in vitro showed a rapid increase in aS gene expression (SNCA) concomitantly with the upregulation of myelination-associated genes such as MPZ and MBP. Transcriptomics and immunostaining analysis of donor-matched transected sural nerve from participants of a nerve transplantation trial (NCT02369003) showed that the levels of aS mRNA and protein were reduced in dedifferentiating (injury-induced) SCs similar to myelin-specific genes. We previously described an unexpected role for aS overexpression as a modulator of neuronal lipid metabolism. aS overexpression in neurons triggered lipid droplets and free cholesterol accumulation. Because myelin is mostly composed of lipids (40 % cholesterol and 40 % phospholipids), we then focused on the identification of lipid metabolism-associated genes. As expected, SC differentiation in vitro was accompanied by the increased expression of the transcription factor MAF1, which is necessary for cholesterol synthesis. Similar to aS, different isoforms of the cholesterol transporter ABCA and the Acetyl-CoA carboxylase gene (ACACB), the rate-limiting step for fatty acid synthesis, were upregulated in differentiated SCs once again highlighting the close relationship between aS and myelin gene expression. Concomitantly, ABCA transporters and LPIN1, the rate-limiting step enzyme of the Kennedy pathway, were reduced in injured nerves. The transcriptomics and immunochemical data analyzed here highlighted the importance of aS as a novel biomarker of the differentiated SC phenotype while raising the interesting hypothesis that its action may be linked to lipid metabolism, as shown previously in the CNS. Further biochemical and cell biology studies are necessary to challenge this hypothesis and explore the biological role of aS in the SC’s lipidome.