Effects of Alpha-Synuclein on Cellular Homeostasis

Abstract

1.1 α-synuclein: A “leading act” in the synapse 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 βand 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 αsynuclein, normally, negatively controls neurotransmitter release.