α-Synuclein is the major protein component of Lewy bodies--the pathological 
hallmark of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Its 
accumulation into intracellular aggregates is implicated in the process of Lewy 
body formation. However, its roles in both normal function, and disease, remain 
controversial. Using a novel model of chronic oxidative stress in cultured 
dopaminergic and cortical neurons, we report that endogenous α-synuclein is 
upregulated in response to low dose toxicity. This response is conserved between 
subpopulations of cortical and dopaminergic neurons, and confers relative 
resistance to apoptosis following secondary insult. Additional acute oxidative 
stress leads to intracellular accumulation of α-synuclein. These punctate 
deposits colocalize with ubiquitin, which is central to proteosome-mediated 
protein degeneration, and is the second major component of Lewy bodies. The 
current results imply that differential levels of α-synuclein expression may 
influence neuronal vulnerability in chronic neurodegenerative diseases. They 
further support a 'two hit' hypothesis for Lewy body formation, whereby mild 
stress causes a protective upregulation of α-synuclein. However, such increased 
levels of α-synuclein may drive its accumulation, following additional toxic 
insult. Finally, these results support a common mechanism for degeneration of 
dopaminergic and cortical neurons, affected in PD, and DLB, respectively.