**6. Acknowledgments**

We would like to thank CNPq for funding Rogério P. Mateus (Master's degree fellowship). We would also like to thank CAPES, FINEP and FUNDUNESP for supporting this work,

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**20** 

*1Japan 2USA* 

*SNCA* **Gene Multiplication:** 

**A Model Mechanism of Parkinson Disease** 

*2Division of Neurogenetics, Department of Neuroscience, Mayo Clinic Jacksonville FL* 

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

PD is the second most frequent neurodegenerative disorder following Alzheimer disease in the elderly. The main symptoms of PD are tremor, bradykinesia, and gait disturbance. PD genetics is categorized into two groups; one is sporadic PD and the other is familial PD. Familial PD has two forms; autosomal dominant heredity (ADPD) and autosomal recessive heredity (ARPD). ADPD has been observed to be caused by mutations in *SNCA* and *LRRK2*. ARPD is caused by homozygous or compound heterozygous mutations in *PARKIN*, *PINK1*, and *DJ-1*(Farrer, 2006). This review will focus on *SNCA* which is located on chromosome 4q21-22 and encodes the 140 amino acid alpha-synuclein protein. *SNCA* has three point mutations; c.88G>C (Ala30Pro), c.188G>A (Glu46Lys) and c.209G>A (Ala53Thr) (Kruger et

*SNCA* duplications and triplications have also been identified as a genetic cause of ADPD. Duplication has two *SNCA* copies on one allele (50% dose increase) and triplication has three, 100 percent dose increase (Figure 1). Rarely, compound heterozygote forms (two duplication alleles) are seen as *SNCA* triplication events (Ikeuchi et al., 2008). These multiplications generate higher *SNCA* expression of mRNA and protein, the so called gene

**1. Introduction** 

recent molecular insights underlying them.

**2.** *SNCA* **triplication and duplication in hereditary PD** 

al., 1998, Zarranz et al., 2004), but they are very rare.

Kenya Nishioka1, Owen A. Ross2 and Nobutaka Hattori1 *1Department of Neurology, Juntendo University School of Medicine, Tokyo* 

