Increased Expression of ABCA8 in Multiple System Atrophy Brain is Associated with Changes in Pathogenic Proteins

Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown aetiology characterised by the accumulation of insoluble alpha-synuclein (alpha-syn) aggregates in the cytoplasm of myelin-producing oligodendrocytes. Dysfunction of the lipid-rich myelin membrane may precede alpha-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 sphingomyelin production in oligodendrocytes in vitro, suggesting a role in myelin formation and maintenance. Objective: We hypothesise that aberrant ABCA8 expression in oligodendrocytes plays a role in the early pathogenesis of MSA by impacting myelin stability and regulation of alpha-syn and p25 alpha. Methods: We measured the expression of ABCA8, alpha-syn and p25 alpha in MSA brains in disease-affected grey matter (GM, putamen and cerebellum), disease-affected white matter (WM, under the motor cortex) and an unaffected brain region (visual cortex). We transfected human oligodendrocytes with ABCA8 and assessed its impact on alpha-syn and p25 alpha expression. Results: ABCA8 expression was significantly increased in the disease-affected GM and WM with no significant change in the unaffected brain region. alpha-syn and p25 alpha expression were significantly increased in the disease-affected WM and GM respectively. Overexpression of ABCA8 in oligodendrocytes caused significant increases in both alpha-syn and p25 alpha expression. Conclusions: These data suggest a direct relationship between the levels of ABCA8 and the ectopic expression of alpha-syn and increased expression of p25 alpha. As these data reflect results found in MSA, we hypothesise that increased ABCA8 may precipitate MSA pathology.