SNCA Gene Multiplication: A Model Mechanism of Parkinson Disease

Parkinson disease (PD) is caused by several pathogenic mutations in genes such as alphasynuclein (SNCA; MIM#163890), Leucine-rich repeat kinase 2 (LRRK2; MIM#609007), PARKIN (parkin; MIM#602544), PTEN-induced kinase 1 (PINK1; MIM#608309), and DJ-1 (MIM#602533) (Farrer, 2006). The alpha-synuclein protein is also a major component of Lewy bodies (LB), the pathologic substrate that is observed in PD patients at autopsy (Spillantini et al., 1997). LB are generally localized to the mid-brain in patients with PD, however a widespread distribution of LB, including cortical regions, is seen in dementia with Lewy bodies (DLB) (Braak et al., 2003, McKeith et al., 2005). The observation of SNCA multiplications co-segregating with PD and dementia in families led to the hypothesis that over-expression of the alpha-synuclein protein is an important mechanism of disease. Herein, we place the gene dosage effect of SNCA in PD in perspective and describe the recent molecular insights underlying them.