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 alpha-synuclein (halpha-syn) in CG-4 oligodendrocytic progenitor cells. CG-4 cells overexpressing halpha-syn (halpha-syn CG-4) demonstrated severely impaired adhesion and increased cell death when plated on fibronectin compared to laminin. The expression of the alphav integrin subunit in whole cell lysates was also significantly downregulated in halpha-syn CG-4. These results demonstrate a cytotoxic consequence of halpha-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 alphav integrin subunit and increased cell death. It may, therefore, be one of the mechanisms underlying the loss of oligodendrocytes in MSA.
Tsuboi
Kyoko
K
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. ktsuboi@vapop.ucsd.edu
Grzesiak
John J
JJ
Bouvet
Michael
M
Hashimoto
Makoto
M
Masliah
Eliezer
E
Shults
Clifford W
CW
D000818:Animals; D000831:Animals, Newborn; D002448:Cell Adhesion / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D039564:Integrin alphaV / Q000378:metabolism; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein
D005353:Fibronectins; D039564:Integrin alphaV; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein