Parkinson's disease (PD) is a neurodegenerative disorder characterized by the 
appearance of intracytoplasmic inclusions called Lewy bodies (LB) in dopamine 
neurons in the substantia nigra and the progressive loss of these neurons. 
Recently, mutations in the alpha-synuclein gene have been identified in 
early-onset familial PD, and alpha-synuclein has been shown to be a major 
component of LB in all patients. Yet, the pathophysiological function of 
alpha-synuclein remains unknown. In this report, we have investigated the toxic 
effects of adenovirus-mediated alpha-synuclein overexpression on dopamine 
neurons in rat primary mesencephalic cultures and in a rat dopaminergic cell 
line - the large T-antigen immortalized, mesencephalon-derived 1RB3AN27 (N27). 
Adenovirus-transduced cultures showed high-level expression of alpha-synuclein 
within the cells. Overexpression of human mutant alpha-synuclein (Ala(53)Thr) 
selectively induced apoptotic programmed cell death of primary dopamine neurons 
as well as N27 cells. The mutant protein also potentiated the neurotoxicity of 
6-hydroxydopamine (6-OHDA). By contrast, overexpression of wild-type human 
alpha-synuclein was not directly neurotoxic but did increase cell death after 
6-OHDA. Overexpression of wild-type rat alpha-synuclein had no effect on 
dopamine cell survival or 6-OHDA neurotoxicity. These results indicate that 
overexpression of human mutant alpha-synuclein directly leads to dopamine neuron 
death, and overexpression of either human mutant or human wild-type 
alpha-synuclein renders dopamine neurons more vulnerable to neurotoxic insults.