Parkinson's disease (PD) is the second most common neurodegenerative disorder primar ily caused by selective dopaminergic cell loss in the midbrain substantia nigra pars compact. However, the exact cause of PD is still unknown. Since identification of monogenic form of PD, the functions of gene products for familial PD (FPD) have provided us good information for studying the mechanisms underlying neurodegeneration in PD. To date, eleven loci have been mapped and among them, six causative genes have been identified as causative genes in familial PD, which have significantly enhanced our understanding of the genetic mechanisms of not only FPD but also sporadic PD. Among the forms of FPD, the causative gene, parkin of AR-JP, representing the most prevalent form of familial PD (Kitada et al., 1998), is of a special interest, because it is liked to ubiquitin-protea-some system (UPS) as an E3 ubiquitin-protein ligase (Shimura et al., 2000), which covalently attaches ubiquitin to target proteins, designating them for degradation by the 26S protea-some (Pickart et al., 2001). These findings suggest that accumulation of the parkin sub-strate(s) due to loss-of-function of parkin induces loss of dopaminergic neurons. Thus, Park2 is caused by failure of proteolysis mediated by UPS (Dawson and Dawson, 2003). Since then, our knowledge of the substrate(s) for parkin has expanded, and indeed at present various putative substrates, such as
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Fig. 1. a-Synuclein inhibits parkin knockdown-induced apoptosis and accumulation of DOPA- and DA-qui-nones. A Effects of overexpression of wild a-SN on as-parkin induced deterioration of cell viability. Differentiated SH-SY5Y cells were treated for 48 hours with as-parkin adenovirus. Cells were coinfected with LacZ and a-SN adenovirus (5 moi) and at the 150 moi titers of as-parkin adenovirus. The cell viability was measured and represented. B Cellular level of DOPA/DA-chromes. After the differentiated SH-SY5Y cells were treated for 36 hours with as-parkin, wild a-SN, LacZ and adenoviruses, cellular DOPA/DA-chromes were measured. Note the profound decrease of DOPA/DA-chromes in a-SN-expressing SH-SY5Y cells. Data are the mean ± SEM of 10 determinations. *P< 0.05 versus control group (Tukey's multiple t test)
CDCrel-1, synphilin-1, a-SN22 (O-glycosy-lated form of a-SN), Pael-R etc, have been identified, but the pathophysiological role of parkin is still poorly understood (see review Hattori and Mizuno, 2004). Furthermore, null mice have no phenotypes for PD although several changes including dopamine metabolism have been reported so far. However, a direct link between these factors and dopaminergic cell death has not yet been reported. The important question of why dopaminergic neurons in the SN are particularly vulnerable to the loss-of-function effect of parkin remains to be determined. Although parkin is expressed ubiquitously in the brain, the pathologic findings of Park2 brains show severe neuronal loss with gliosis in the SN and mild neuronal loss in the locus coeruleus (LC), suggesting that the pathological change of Park2 brain is mainly in the SN. To investigate such selec tive neuronal loss, we established a good in vitro model by parkin knock down using full length antisense parkin.
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