Alpha-synuclein overexpression in oligodendrocytic cells results in impaired adhesion to fibronectin and cell death

The cardinal pathological features of multiple system atrophy (MSA) are the presence of glial cytoplasmic inclusions (GCIs) in oligodendrocytes and loss of oligodendrocytes. To understand the mechanisms underlying MSA, we examined the effects of overexpression of human α-synuclein (hα-syn) in CG-4 oligodendrocytic progenitor cells. CG-4 cells overexpressing hα-syn (hα-syn CG-4) demonstrated severely impaired adhesion and increased cell death when plated on fibronectin compared to laminin. The expression of the αv integrin subunit in whole cell lysates was also significantly downregulated in hα-syn CG-4. These results demonstrate a cytotoxic consequence of hα-syn overexpression in CG-4. This cytotoxicity appears to be the result of alterations in cell-extracellular matrix interactions, where impaired adhesion to fibronectin is associated with downregulation of the αv integrin subunit and increased cell death. It may, therefore, be one of the mechanisms underlying the loss of oligodendrocytes in MSA.