PARK1/4 (SNCA/Alpha-Synuclein)

The PARK1 locus was initially found in an Italian family exhibiting autosomal dominant PD (Golbe et al., 1990; Polymeropoulos et al., 1996). Subsequent studies in the original family and additional European families identified mutations (A53T, A30P and E46K) in the SNCA gene coding for the protein alpha-synuclein as the underlying genetic cause (Polymeropoulos et al., 1997; Krüger et al., 1998; Zarranz et al., 2004). In addition to these missense mutations, genomic rearrangement in the form of duplication and triplication of the wildtype SNCA gene was also found to cause PD in several families that were originally defined by the PARK4 locus (Singleton et al., 2003; Ibáñez et al., 2004; Chartier-Harlin et al., 2004).

Alpha-synuclein gene triplication (pink) on chromosome 4.Image from NINDS, NIHMutations within the gene for alpha-synuclein can lead to disease with features of PD or dementia with Lewy bodies (Gasser, 2009). Both are characterized by the presence of Lewy bodies and Lewy neurites, and alpha-synuclein (along with ubiquitin) is a major component of these histopathological features (Braak and Del Tredici, 2009). In people with SNCA gene multiplication, a triplication of the gene correlates with an apparent early age of onset, while duplication leads to a more typical late-onset PD (Chartier-Harlin et al., 2004).

Variation within the alpha-synuclein gene may also act as a risk factor in sporadic PD. A dinucleotide repeat sequence, REP-1, within the alpha-synuclein gene promoter region has been associated with PD risk (Maraganore et al., 2006). Additional variants within the alpha-synuclein gene, including at the 5' and 3' regions, have also been linked with higher PD risk (Mueller et al., 2005; Winkler et al., 2007; Pankratz et al., 2009).

The normal function of alpha-synuclein remains unknown, though it is thought to play an important role in synaptic function or lipid binding. It is natively found in an unfolded state but is highly prone to aggregation, stabilized by folding to a beta-sheet conformation. Alpha-synuclein aggregation is differentially modulated by different PD-associated mutations (Cookson, 2009).

Given its clear role in genetic forms of PD and presence in Lewy bodies, alpha-synuclein has become a major target for therapeutic development.