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**8** 

*Greece* 

**Effects of Alpha-Synuclein on** 

Kostas Vekrellis, Georgia Minakaki and Evangelia Emmanouilidou

*Department of Neurosciences, Biomedical Research Foundation of the Academy of Athens* 

α-Synuclein is a relatively abundant 140-residue neuronal protein physiologically found in presynaptic neuronal terminals (Abeliovich et al., 2000; Spillantini, Crowther, Jakes, Hasegawa, & Goedert, 1998; Wacker, Zareie, Fong, Sarikaya, & Muchowski, 2004). αsynuclein belongs to a highly conserved family of proteins which includes β- and γ-synucleins. It is an intrinsically unfolded, or natively unfolded, protein, meaning that in its purified form at neutral pH it lacks an ordered secondary or tertiary structure (Trojanowski & Lee, 1998). Three missense point mutations (A53T, A30P and E46K) have been identified in families with autosomal dominant Parkinson's disease (PD) (Figure 1) (Chartier-Harlin et al., 2004; Kruger et al., 1998; Polymeropoulos et al., 1997). In addition, duplications and triplications in the gene encoding for α-synuclein have been shown to cause rare familial forms of PD, suggesting that the levels of the protein are critical in the pathogenesis of the disease (Singleton et al., 2003; Zarranz et al., 2004). Over-expression of mutant α-synuclein in transgenic mice under various promoters presents only certain aspects of PD and some have been shown to lead to neurodegeneration (reviewed in Sulzer, 2010). Knockout mice for α-synuclein do not exhibit severe neuropathological alterations but, at least in the nigrostriatal dopaminergic system, they show an enhancement of response to paired electrical stimuli, suggesting that α-

> **NH2 COOH 1 140**

> > **domain (NAC region)**

Fig. 1. Schematic representation of α-synuclein showing the basic regions of the protein and

With respect to neurotransmission, it has been recently reported that excessive αsynuclein induces a series of pathologic changes, including deficits in neurotransmitter release. In a recent study, Nemani et al. (2010) showed that following only modest

**61 95**

**acidic domain**

**1. Introduction** 

**1.1** α**-synuclein: A "leading act" in the synapse** 

synuclein, normally, negatively controls neurotransmitter release.

**A30P A53T**

the point mutations that have been linked with familial PD.

α**-helical domain hydrophobic**

**E46K**

**Cellular Homeostasis** 

alpha-synuclein binding to synaptic membranes by cytosolic factors. BMC Neurosci 9:92.

