Alpha Synuclein: Mutations
The differing characteristics of healthy and pathogenic α-synuclein has led researchers to question the variances between the two forms of the protein. After a genetic analysis in 1997, the identification of point mutations within the SNCA gene in familial Parkinson’s served as the preliminary link between α-synuclein and PD. Since then there have been six missense mutations in the SNCA gene linked to the autosomal dominant form of PD; Ala53Thr, Ala30Pro, Glu46Lys, His50Gln, Gly51Asp, and Ala53Glu4. Furthermore, the discovery of PD patients with a duplication or triplication of the SNCA gene (PARK4 locus) reinforced the association between α-synuclein and PD, and suggested that higher amounts of the wild-type protein could trigger the disease. Individuals who developed a triplication of the SNCA gene, as opposed to a duplication, displayed more severe symptoms including early-onset parkinsonism with dementia. This indicates that there is a “dose dependent” correlation between the progression of PD and SNCA gene dosage (Dehay et al., 2015).