Alpha-synuclein and familial Parkinson's disease.

Mutations in five genes have been found to cause Parkinson’s disease (PD) in a small subset of patients with disease (<5% of cases). One of these genes, alpha-synuclein (SNCA), has been reported to act as both a causative and a susceptibility gene for PD. Missense mutations,1–3 as well as whole gene dosage changes,4–6 segregate with disease in an autosomal pattern of inheritance. Variation in the promoter region of SNCA, specifically the dinucleotide repeat polymorphism known as Rep1, has been reported to increase the risk for PD.7 A meta-analysis has further bolstered evidence that Rep1 is associated with a slight, but significant, increase in the risk of PD.8 Variation in the 3′ region of SNCA has also been associated with risk for PD.9 The two domains flanking the Rep1 repeat appear to interact with each other to enhance expression of SNCA, while Rep1 acts as a negative modulator.10 In addition, different alleles can vary the expression levels of SNCA in SH-SY5Y cells by up to threefold.10 There is also evidence from a genomewide study of gene expression that variation at the 3′ end of the gene can affect expression levels of SNCA.11 Because a triplication or a duplication of the normal gene can lead to a highly penetrant form of PD, and since a triplication (four copies of the gene) tends to lead to an earlier disease onset than a duplication (three copies of the gene), it is possible that even a subtle increase in expression could, over the course of many decades, predispose an individual to develop PD. The purpose of this study is to test in familial PD whether: (1) dosage and coding changes in SNCA are a more frequent cause of PD than in sporadic cases; (2) Rep1 allele-length variability is associated with PD susceptibility or age of onset; and (3) variation in the 3′ region of SNCA is associated with PD susceptibility or age of onset.