Two different mutations have been identified in the a-synuclein gene (PARK1) on chromosome 4q21. In 1997, the A53T mutation was found in a large Italian/American family (Golbe et al., 1990) as well as in three unrelated families of Greek descent, in which Parkinson's disease was inherited with an autosomal dominant pattern (Polymeropoulos et al., 1997). 

The second mutation, the A30P mutation, has been reported in one German family (Kruger et al., 1998). Clinical characteristics of the patients with the A53T mutation differed from sporadic Parkinson's disease with respect to a slightly younger age at onset, a considerably lower prevalence of tremor and a more rapid clinical deterioration.

a-Synuclein is abundantly present in brain, and, upon the identification of the mutations in its encoding gene, was identified to be a principal component of Lewy bodies (Spillantini et al., 1997). In vitro experiments suggested that the mutant protein facilitates fibril formation, giving rise to Lewy bodies. The A53T-mutated a-synuclein formed Æbrils more easily than the A30P mutant (Conway et al., 1998). The lesser complexity of the A30P-linked clinical phenotype (resembling typical Parkinson's disease) may therefore refect its lower degree of a-synuclein fibrillogenesis in vitro.

Experiments have shown that α-synuclein can be phosphorylated by both src family of protein-tyrosine kinases on tyrosine 125, casein kinase 1 and 2 on serine 129 (Ellis CE. et al., 2001; Okochi M. et al., 2000). More excitingly, phosphorylated α-synuclein has been found to be highly enriched in the insoluble fractions of synucleinopathy brains and these α-synuclein species have been shown to be ubiquitin positive (Hasegawa M. et al., 2002). How the phosphorylation of α-synuclein is related to the pathogenesis of PD awaits further investigation.

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