Increased expression of α-synuclein by SNCA duplication is associated with resistance to toxic stimuli.

Duplication of alpha-synuclein gene (SNCA) is a recognized cause of Parkinson's disease (PD). However, the penetrance in families with SNCA duplication is as low as 30%, indicating that factors other than the SNCA gene dosage have an important role in neuronal death. In this study, using lymphoblastoid cell lines (LCLs) derived from a parkinsonian kindred with SNCA duplication, we examined whether there is difference in (1) the level of SNCA mRNA and protein expression and cell viability and (2) the vulnerability to various insults relevant to PD between a patient, asymptomatic carrier, and unaffected control. Expression of SNCA mRNA and protein increased in the LCLs from subjects with SNCA gene duplication, irrespective of the disease status. In the absence of treatment, LCLs from the patient and carrier showed decreased viability compared with the LCL from the control. The LCL from the patient also showed decreased viability compared to the carrier. When susceptibility to various insults including lactacystin, dexamethasone, 3-methyladenine, H(2)O(2), and rotenone was examined, surprisingly, the LCL from the patient was more resistant than the LCL from the control to all agents except for lactacystin. This study shows that both intrinsic and extrinsic factors and their interaction have important roles in cell death and in the development of PD and further indicates that the relationship between cell death and the level of alpha-synuclein may be more complicated than previously thought.