α-Synuclein gene duplications in sporadic Parkinson disease

Abstract

Heritability of Parkinson disease (PD) has long been disputed since patients seldom had a positive family history of the disease. Nevertheless, during the last decade genetic linkage studies in rare Mendelian PD families identified six genes in which mutations were associated with PD.1 In fact, most current knowledge of molecular pathogenesis of PD results from functional studies of the proteins encoded by these PD genes. At present, our improved insight into genetic risk for PD contributes to a more accurate diagnosis and provides rationales for new therapeutic approaches based on powerful model systems of mutated PD genes. The first PD gene identified was the α-synuclein gene ( SNCA ) in which a pathogenic missense mutation—p.Ala53Thr (c.157G>A)—segregated with PD in the autosomal dominant Contursi kindred.2 Two more missense mutations were identified in a German (c.88G>C; p.Ala30Pro) and a Spanish (c.136G>A; p.Glu46Lys) family.1 These mutations supported a direct link between α-synuclein dysfunction and the appearance of Lewy bodies of this protein in PD brains, and are expected to cause PD via a toxic gain-of-function of mutant SNCA protein. Later, a major role for wild type SNCA in PD pathogenesis …