Ft

W445X

W453X

1385insA 1276-77delGA

RING

RING

Fig. 3. Schematic presentation of exons of parkin and missense mutations, nonsense mutations, and small deletions summarized from the following literature, i.e., Hattori et al. (1998), Abbas et al. (1999), Liicking et al. (2000), Oliviera et al. (2003), and Hedrick et al. (2004). Missense mutations are shown above the exons and nonsense mutations and small deletions below the exons. UBL ubiquitin-like domain, RING RING domain,

IBR in-between RINGs metabolism, immunity, and neurodegeneration (Tanaka et al., 2004). The ubiquitin system consists of three enzymes, i.e., the ubiquitin activating enzyme (E1), the ubiquitin conjugating enzyme (E2), and the ubiquitin-protein ligase (E3). The E3 transfers ubiquitin molecules to target proteins forming a poly-ubiquitin chain which is recognized by 26S proteasome as the proteolytic signal. Therefore, in the presence of mutated parkin proteins, accumulation of parkin-substrate proteins is expected to be the major cause of nigral neuronal death. However, to date there is no clear immunohistochemical evidence to indicate accumulation of parkin-substrates in PARK2 patients, despite many parkin-interacting proteins have been reported such as CDCrel-1 (Zhang et al., 2000), glycosylated alpha-synuclein (Shimura et al., 2001), PAEL receptor (Imai et al., 2001), and syn-philin-1 (Chung et al., 2001). We recently reported that parkin-knock down SH-SY5Y cells showed increased formation of dopa-mine/dopa-derived quinones and apoptotic cell death (Machida et al., 2005); these qui-nones appeared to be the mediator of cell death. Thus parkin appears to have a potent anti-oxidative property. As in the case of sporadic PD, oxidative damage may be an important mechanism of nigral neuronal death in PARK2.

Other mechanism that has been postulated is polyubiquitylation at the lysine-63 residue of the ubiquitin molecules. Polyubiquitin chains formed via the lysine-48 residue of the ubiquitin molecule mainly become a marker for proteolytic attack by the 26S protea-some. On the other hand, lysine 63-linked polyubiquitylation has many biological roles other than proteolysis, such as endocytosis, DNA repair, translation, IkB activation, DNA silencing, virus budding, protein sorting, and protein trafficking (Tanaka et al., 2004). Parkin promotes not only polyubiquitylation at lysine-48 but also at lysine-63. Recently, Lim et al. (2005) reported that parkin enhanced lysine-63 mediated polyubiquitylation of synphilin-1. Thus this is a novel aspect of the functions of parkin protein, however, exact molecular mechanism of nigral neurodegeneration in PARK2 is still open to question.

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