Effect of the overexpression of wild-type or mutant α-synuclein on cell susceptibility to insult
Version of Record online: 20 DEC 2001
Journal of Neurochemistry
Volume 76, Issue 4, pages 998–1009, February 2001
How to Cite
Lee, M., Hyun, D.-H., Halliwell, B. and Jenner, P. (2001), Effect of the overexpression of wild-type or mutant α-synuclein on cell susceptibility to insult. Journal of Neurochemistry, 76: 998–1009. doi: 10.1046/j.1471-4159.2001.00149.x
- Issue online: 20 DEC 2001
- Version of Record online: 20 DEC 2001
- Received July 31, 2000; revised manuscript received September 25, 2000; accepted September 29, 2000.
- familial Parkinson's disease;
- mutant α-synuclein;
- oxidative stress;
- wild-type α-synuclein
Mutations in α-synuclein (A30P and A53T) are involved in some cases of familial Parkinson's disease (FPD), but it is not known how they result in nigral cell death. We examined the effect of α-synuclein overexpression on the response of cells to various insults. Wild-type α-synuclein and α-synuclein mutations associated with FPD were overexpressed in NT-2/D1 and SK-N-MC cells. Overexpression of wild-type α-synuclein delayed cell death induced by serum withdrawal or H2O2, but did not delay cell death induced by 1-methyl-4-phenylpyridinium ion (MPP+). By contrast, wild-type α-synuclein transfectants were sensitive to viability loss induced by staurosporine, lactacystin or 4-hydroxy-2-trans-nonenal (HNE). Decreases in glutathione (GSH) levels were attenuated by wild-type α-synuclein after serum deprivation, but were aggravated following lactacystin or staurosporine treatment. Mutant α-synucleins increased levels of 8-hydroxyguanine, protein carbonyls, lipid peroxidation and 3-nitrotyrosine, and markedly accelerated cell death in response to all the insults examined. The decrease in GSH levels was enhanced in mutant α-synuclein transfectants. The loss of viability induced by toxic insults was by apoptosic mechanism. The presence of abnormal α-synucleins in substantia nigra in PD may increase neuronal vulnerability to a range of toxic agents.