Morphology of Lewy Pathology

Lewy pathology chiefly consists of misfolded and aggregated forms of the presynaptic neuronal protein α-synuclein that belongs to a larger and highly conserved family of proteins, including β-synuclein and γ-synuclein or breast cancer-specific gene 1 (BCSG1 or persyn). In its natively unfolded state, α-synuclein ranges from 127 to 140 amino acids in length and is soluble in cytosol. The protein contains a lipid binding repeat region followed by a hydrophobic area—the non-Aβ component (NAC) region between residues 61 and 95—and a negatively charged carboxy terminal (Fig. 1e). α-Synuclein can be phosphorylated, nitrated, and is transported by axoplasmic flow (Jensen and Gai 2001; Anderson et al. 2006). It may be involved in the transport of synaptic vesicles and it probably also is capable of microtubule-polymerizing activity. Additional functions are currently unknown (Wakabayashi et al. 1992, 1998; Spill-antini et al. 1997; Baba et al. 1998; Clayton and George 1998, 1999; Lavedan 1998; Trojanowski and Lee 1998, 2000, 2003; Golbe 1999; Golbe and Mouradian 2004; Duda et al. 2000; Goldberg and Lansbury 2000; Giasson et al. 2000a, 2001; Galvin et al. 2001; Goedert 2001; Walker and LeVine 2001; Fujiwara et al. 2002; Alim et al. 2004; Norris et al. 2004; von Bohlen und Halbach 2004; Chua and Tang 2006; Gitler and Shorter 2007; Yu et al. 2007; Klegeris et al. 2008; McGeer and McGeer 2008).

Since α-synuclein exists in many, but not all, nerve cell types in the human nervous system, it can be inferred that all of the vulnerable neurons in sPD require sufficient amounts of the natively unfolded protein to become involved (Braak et al. 2001).