Genetic variability in the promoter and 3' region of the SNCA gene coding alpha-synuclein modulates the risk to develop sporadic Parkinson's disease (PD). Whether this is mediated by regulating alpha-synuclein expression levels remains unknown. Therefore, we analyzed levels of alpha-synuclein in blood and human post mortem brain tissue including the substantia nigra using quantitative real-time reverse transcriptase-polymerase chain reaction and enzyme linked immunosorbent assay in vivo. Single nucleotide polymorphism (SNP) rs356219, a tagging SNP for a disease-associated haplotype in the 3' region of the SNCA gene, has a significant effect on SNCA mRNA levels in the substantia nigra and the cerebellum. Further, the "protective" genotype 259/259 of the PD-associated promoter repeat NACP-Rep1 is associated with lower protein levels in blood than genotypes 261/261, 259/261, and 259/263. In conclusion, we provide evidence that alpha-synuclein levels are influenced by genetic variability in the promoter and 3' region of the SNCA gene in vivo.

Background: The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD).Objective: To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET).Design: Longitudinal prospective cohort study with a follow-up period of 64.5 ± 22.6 months (mean ±SD).Setting: University hospital. Patients: A consecutive sample of patients with PD (N=31; age at symptom onset, 53.6 ± 11.3 years) with a wide range of symptom duration and severity at the time of study entry. Interventions: Investigation by serial fluorodopa F 18 ([ 18 F]fluorodopa) PET as a marker for striatal dopaminergic function. Main Outcome Measures: Changes in caudate and putaminal [ 18 F]fluorodopa influx constant (K i ) values.Results: In patients with PD, the decline rate of putaminal [ 18 F]fluorodopa K i correlated inversely with disease duration before study inclusion (r=−0.46, P =.01) and positively with baseline K i values (r =0.44, P =.01), indicating a negative exponential loss of dopamine neurons. Annual disease progression rates ranged from 4.4% in the caudate nucleus to 6.3% in the putamen. A mean preclinical period of 5.6±3.2 years was calculated with symptom onset at a putaminal K i threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [ 18 F]fluorodopa PET was found to increase strongly with the preceding symptom duration of study subjects. Conclusion:These data suggest that the neurodegenerative process in PD follows a negative exponential course and slows down with increasing symptom duration, contradicting the long-latency hypothesis of PD.

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