Increased expression of ABCA8 in multiple system atrophy brain is associated with changes in pathogenic proteins

Abstract

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown aetiology characterised by the accumulation of insoluble α-synuclein (α-syn) aggregates in the cytoplasm of myelin-producing oligodendrocytes. Dysfunction of the lipid-rich myelin membrane may precede α-syn pathology in MSA pathogenesis. ATP-binding cassette transporter A8 (ABCA8) is a little-studied lipid transporter, which has recently been found to be highly expressed in oligodendrocyte-rich white matter regions of the human brain. ABCA8 expression promotes sphingmyelin production in oligodendrocytes in vitro, suggesting a role in myelin formation and maintenance. We hypothesise that aberrant ABCA8 expression in oligodendrocytes plays a role in the early pathogenesis of MSA by impacting myelin stability and regulation of α-syn and p25α. Firstly, we measured the regional expression of α-syn and p25α in certain MSA white matter (WM) and grey matter (GM) brain regions. Next we measured the expression of ABCA8 in MSA and control brains and found that it was significantly increased in MSA brains in disease-affected GM (putamen and cerebellum) and disease-affected WM (under the motor cortex) with no significant change in an unaffected brain region (visual cortex). We then transfected human MO3.13 oligodendrocytes with ABCA8 and assessed the impact of ABCA8 expression on α-syn and p25α expression. Overexpression of ABCA8 in the cells caused significant increases in both α-syn and p25α expression, suggesting a direct relationship between the levels of this sphingomyelin transporter and the ectopic expression of α-syn and increased expression of p25α. As this data reflects results found in MSA, we hypothesise that increased ABCA8 may precipitate MSA pathology.