Mutations in the alpha-synuclein gene have been linked to rare cases of familial 
Parkinson's disease (PD). Alpha-synuclein is a major component of Lewy bodies 
(LB), a pathological hallmark of PD. Transgenic mice and Drosophila expressing 
either wild-type or mutant human alpha-synuclein develop motor deficits, LB-like 
inclusions in some neurons, and neuronal degeneration. However, the relationship 
between abnormal aggregates of alpha-synuclein and human dopamine (DA) neuron 
degeneration remains unclear. In this report, we have investigated the influence 
of alpha-synuclein expression on DA neurons in primary culture of embryonic 
human mesencephalon. Two days after culture, human DA cells were transduced with 
wild-type or mutant human (Ala(53)Thr) alpha-synuclein adenoviruses and 
maintained for 5 days. Overexpression of mutant and wild-type human 
alpha-synuclein resulted in 49% (P<0.01) and 27% (P<0.05) loss of DA neurons, 
respectively, while not affecting viability of other cells in the culture. 
Overexpression of rat alpha-synuclein or GFP (green fluorescent protein) had no 
effect on DA neuron survival. Cytoplasmic inclusions of alpha-synuclein were 
detected immunohistochemically in DA cells transduced with mutant human 
alpha-synuclein, but not wild-type alpha-synuclein. These results show that 
overexpression of human alpha-synuclein, particularly the mutant form, can cause 
human DA neuron death, suggesting that alpha-synuclein may have a primary role 
in the pathogenesis of PD.