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 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 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 α-syn and p25α.


METHODS
We measured the expression of ABCA8, α-syn and p25α 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 α-syn and p25α expression.


RESULTS
ABCA8 expression was significantly increased in the disease-affected GM and WM with no significant change in the unaffected brain region. α-syn and p25α expression were significantly increased in the disease-affected WM and GM respectively. Overexpression of ABCA8 in oligodendrocytes caused significant increases in both α-syn and p25α expression.


CONCLUSIONS
These data suggest a direct relationship between the levels of ABCA8 and the ectopic expression of α-syn and increased expression of p25α. As these data reflect results found in MSA, we hypothesise that increased ABCA8 may precipitate MSA pathology.
Neuroscience Research Australia, Sydney, NSW, Australia School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Jonathan M
JM
Bleasel
Jen-Hsiang T
JH
Hsiao
Glenda M
GM
Halliday
Woojin Scott
WS
Kim
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D001923:Brain Chemistry / Q000235:genetics*; D002478:Cells, Cultured; D003199:Computer Systems; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000378:metabolism*; D009186:Myelin Sheath / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009836:Oligodendroglia / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D051844:alpha-Synuclein / Q000378:metabolism
C582675:ABCA8 protein, human; D018528:ATP-Binding Cassette Transporters; D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D051844:alpha-Synuclein; D012313:RNA